6-membered heterocyclic compounds useful for selective inhibition of the coagulation cascade

ABSTRACT

The present invention relates to compounds, and prodrugs thereof, compositions and methods useful for preventing and treating thrombotic conditions in mammals. The compounds of the present invention, and prodrugs thereof, selectively inhibit certain proteases of the coagulation cascade.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority from Provisional Application Ser. No.60/326,721 filed Oct. 3, 2001, No. 60/338,623 filed Oct. 24, 2001, No.60/332,857 filed Nov. 6, 2001, No. 60/350,052 filed on Nov. 7, 2001, andNo. 60/332,107 and 60/331,891 both filed on Nov. 21, 2001, which are allhereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to compounds, compositions and methods forpreventing and treating thrombotic conditions such as coronary arteryand cerebrovascular disease. More particularly, the invention relates tocompounds, and prodrugs thereof, that selectively inhibit serineproteases of the coagulation cascade.

BACKGROUND OF THE INVENTION

Hemorrhage, intravascular thrombosis, and embolism are common clinicalmanifestations of many diseases (see R. I. Handin in Harrison'sPrinciples of Internal Medicine (J. D. Wilson, et al. eds., 12th ed.1991) New York, McGraw-Hill Book Co., pp. 348-351). The normalhemostatic system limits blood loss by precisely regulated interactionsbetween components of the vessel wall, circulating blood platelets, andplasma proteins. Unregulated activation of the hemostatic system,however, may cause thrombosis, which can reduce blood flow to criticalorgans like the brain and myocardium.

Physiological systems control the fluidity of blood in mammals (see P.W. Majerus, et al. in Goodman & Gilman's The Pharmacological Basis ofTherapeutics (J. G. Hardman & L. E. Limbird, eds., 9th ed. 1996) NewYork, McGraw-Hill Book Co., pp. 1341-1343). Blood must remain fluidwithin the vascular systems and yet quickly be able to undergohemostasis. Hemostasis, or clotting, begins when platelets first adhereto macromolecules in subendothelian regions of injured and/or damagedblood vessels. These platelets aggregate to form the primary hemostaticplug and stimulate local activation of plasma coagulation factorsleading to generation of a fibrin clot that reinforces the aggregatedplatelets. Plasma coagulation factors, also referred to as proteasezymogens, include factors II, V, VII, VIII, IX, X, XI, and XII. Thesecoagulation factors or protease zymogens are activated by serineproteases leading to coagulation in a so called “coagulation cascade” orchain reaction.

Coagulation or clotting occurs in two ways through different pathways.An intrinsic or contact pathway leads from XII to XIIa to XIa to IXa andto the conversion of X to Xa. Factor Xa in combination with factor Vaconverts prothrombin (II) to thrombin (IIa) leading to conversion offibrinogen to fibrin. Polymerization of fibrin leads to a fibrin clot.An extrinsic pathway is initiated by the conversion of coagulationfactor VII to VIIa by factor Xa. Factor VIIa, a plasma protease, isexposed to, and combines with its essential cofactor tissue factor (TF)which resides constitutively beneath the endothelium. The resultingfactor VIIa/TF complex proteolytically activates its substrates, factorsIX and X, triggering a cascade of reactions that leads to the generationof thrombin and a fibrin clot as described above.

While clotting as a result of an injury to a blood vessel is a criticalphysiological process for mammals, clotting can also lead to diseasestates. A pathological process called thrombosis results when plateletaggregation and/or a fibrin clot blocks (i.e., occludes) a blood vessel.Arterial thrombosis may result in ischemic necrosis of the tissuesupplied by the artery. When the thrombosis occurs in a coronary artery,a myocardial infarction or heart attack can result. A thrombosisoccurring in a vein may cause tissues drained by the vein to becomeedematous and inflamed. Thrombosis of a deep vein may be complicated bya pulmonary embolism. Preventing or treating clots in a blood vessel maybe therapeutically useful by inhibiting formation of blood plateletaggregates, inhibiting formation of fibrin, inhibiting thrombusformation, inhibiting embolus formation, and for treating or preventingunstable angina, refractory angina, myocardial infarction, transientischemic attacks, atrial fibrillation, thrombotic stroke, embolicstroke, deep vein thrombosis, disseminated intravascular coagulation,ocular build up of fibrin, and reocclusion or restenosis of recanalizedvessels.

In order to treat such conditions, researchers have sought to discoverchemical compounds that efficaciously and selectively control theclotting process. In addition, such compounds may provide a betterunderstanding of the pathways involved in the coagulation process.

Thus far, many of the compounds that have been discovered possess apolar or basic functional group which is integrally responsible for thedesired biological activity. Frequently, this polar functional group isa nitrogen atom of, for example, a guanidine, alkyl-amidine oraryl-amidine group. Because these functionalities are highly basic, theyremain protonated at physiologically relevant pH's. The ionic nature ofsuch protonated species hinders their permeability across lipophilicmembranes, which can reduce bioavailability when the pharmaceuticalagent is administered orally.

In order to circumvent such a problem, it is often advantageous toperform a derivatization or chemical modification of the polarfunctionality such that the pharmaceutical agent becomes neutrallycharged and more lipophilic, thereby facilitating absorption of thedrug. However, for the derivatization to be useful, the derivatizationmust be bioconvertable at the target site or sites of desiredpharmacological activity and cleaved under normal physiologicalconditions to yield the biologically active drug. The term “prodrug” hasbeen used to denote such a chemically modified intermediate.

SUMMARY OF THE INVENTION

Among the various aspects of the present invention, therefore, is theprovision of compounds useful for selective inhibition of certainenzymes that act upon the coagulation cascade thereby preventing andtreating thrombotic conditions in mammals.

Another aspect of the present invention is the provision of prodrugcompounds useful for selective inhibition of certain enzymes that actupon the coagulation cascade thereby preventing and treating thromboticconditions in mammals. In general, these prodrug compounds undergohydrolysis, oxidation, reduction or elimination at a derivatized amidinegroup to yield the active compound.

Briefly, therefore, the present invention is directed to a compound, perse, to the prodrug of the compound, to pharmaceutical compositionscomprising the compound or prodrug and a pharmaceutically acceptablecarrier, and to methods of use. The compound corresponds to formula (1):

wherein:

X₁, X₂, X₃, X₄, X₅, and X₆ are each ring atoms defining a 6-memberedheterocyclic ring;

X₁, X₃, and X₄ are independently carbon or nitrogen;

X₂, X₅, and X₆ are independently carbon, nitrogen, oxygen or sulfur,where X₅ and X₆ are optionally substituted with a halogen, provided nomore than 4 of X₁, X₂, X₃, X₄, X₅, and X₆ are sp² hybridized;

L₁, L₃ and L₄ are linkages through which Z₁, Z₃, and Z₄, respectively,are covalently bonded to different ring atoms of the 6-memberedheterocyclic ring defined by X₁, X₂, X₃, X₄, X₅, and X₆, wherein Z₁ iscovalently bonded to X₁, Z₃ is covalently bonded to X₃, and Z₄ iscovalently bonded to X₄, each of L₁, L₃ and L₄ independently being acovalent bond or comprising one or more atoms through which Z₁, Z₃, andZ₄ are covalently bonded to X₁, X₃ and X₄, respectively;

Z₁ is hydrocarbyl or substituted hydrocarbyl;

Z₂ is hydrogen, an electron pair, or a hydrogen bond acceptor covalentlyor datively bonded to X₂;

Z₃ comprises a 5- or 6-membered heterocyclic or aromatic ringsubstituted with an amidine or a derivatized amidine group, the ringatoms of the 5- or 6-membered heterocyclic or aromatic ring of Z₃ beingcarbon, sulfur, nitrogen, or oxygen wherein the 5- or 6-membered ring isoptionally substituted at any position with halogen, hydroxy, haloalkyl,alkyl, carboxy, alkoxycarbonyl, or hydrocarbyloxy; and

Z₄ comprises a 5- or 6-membered heterocyclic or carbocyclic ring, thering atoms of the 5- or 6-membered heterocyclic or carbocyclic ring ofZ₄ being carbon, nitrogen, oxygen, or sulfur.

Other aspects and features of this invention will be in part apparentand in part pointed out hereafter.

Abbreviations and Definitions

The term “elimination” as used herein is generally meant to encompassany one or more of the following reactions: (1) a reaction that resultsin a compound fragmenting into two or more compounds; and (2) a reactionthat results in one or more groups being removed from a compound withoutbeing replaced by other groups.

The term “oxidation” as used herein is generally meant to encompass anyone or more of the following reactions: (1) a reaction that results inan increase in the oxidation number of an atom in a compound, whetherthe atom is uncharged or charged and whether free or covalently bound;(2) a reaction that results in the loss of hydrogen from a compound; (3)a reaction that results in the loss or removal of one or more electronsfrom a compound, with or without concomitant loss or removal of a protonor protons; (4) the action or process of reacting a compound withoxygen; and (5) a reaction that results in the addition of one or moreoxygen atoms to a compound.

The term “reduction” as used herein is generally meant to encompass anyone or more of the following reactions: (1) any reaction which resultsin a decrease in the oxidation number of an atom in a compound; and (2)any reaction that results in oxygen being withdrawn from, hydrogen beingadded to, or an electron being added to (with or without the addition ofa proton) a compound.

The term “hydrolysis” as used herein is generally meant to encompass anyone or more of the following reactions: (1) any reaction which resultsin the addition of a nucleophile to a compound to form a new bond withconcurrent loss of a group from the compound; (2) any reaction whichresults in the addition of water to a compound; and (3) any reactionthat results in the rupture of one or more chemical bonds by reactionwith, and involving the addition of, the elements of water.

The term “physiological conditions” are those conditions characteristicto an organism's (to a human beings) healthy or normal functioning.

The terms “hydrocarbon” and “hydrocarbyl” as used herein describeorganic compounds or radicals consisting exclusively of the elementscarbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, andaryl moieties. These moieties also include alkyl, alkenyl, alkynyl, andaryl moieties substituted with other aliphatic or cyclic hydrocarbongroups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwiseindicated, these moieties preferably comprise 1 to 20 carbon atoms.

The “substituted hydrocarbyl” moieties described herein are hydrocarbylmoieties which are substituted with at least one atom other than carbon,including moieties in which a carbon chain atom is substituted with aheteroatom such as nitrogen, oxygen, silicon, phosphorus, boron, sulfur,or a halogen atom. Exemplary substituted hydrocarbyl moieties include,heterocyclo, alkoxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl,aryloxyalkyl, hydroxyalkyl, protected hydroxyalkyl, keto, acyl,nitroalkyl, aminoalkyl, cyano, alkylalkylthio, arylalkylthio, ketals,acetals, amides, acids, esters and the like.

The term “heteroatom” shall mean atoms other than carbon and hydrogen.

Unless otherwise indicated, the alkyl groups described herein arepreferably lower alkyl containing from one to eight carbon atoms in theprincipal chain and up to 20 carbon atoms. They may be straight orbranched chain or cyclic and include methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl, hexyl and the like.

Unless otherwise indicated, the alkenyl groups described herein arepreferably lower alkenyl containing from two to eight carbon atoms inthe principal chain and up to 20 carbon atoms. They may be straight orbranched chain or cyclic and include ethenyl, propenyl, isopropenyl,butenyl, isobutenyl, hexenyl, and the like.

Unless otherwise indicated, the alkynyl groups described herein arepreferably lower alkynyl containing from two to eight carbon atoms inthe principal chain and up to 20 carbon atoms. They may be straight orbranched chain and include ethynyl, propynyl, butynyl, isobutynyl,hexynyl, and the like.

The terms “aryl” or “ar” as used herein alone or as part of anothergroup denote optionally substituted homocyclic aromatic groups,preferably monocyclic or bicyclic groups containing from 6 to 12 carbonsin the ring portion, such as phenyl, biphenyl, naphthyl, substitutedphenyl, substituted biphenyl or substituted naphthyl. Phenyl andsubstituted phenyl are the more preferred aryl.

The terms “halogen” or “halo” as used herein alone or as part of anothergroup refer to chlorine, bromine, fluorine, and iodine.

The terms “heterocyclo” or “heterocyclic” as used herein alone or aspart of another group denote optionally substituted, fully saturated orunsaturated, monocyclic or bicyclic, aromatic or nonaromatic groupshaving at least one heteroatom in at least one ring, and preferably 5 or6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygenatoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring,and may be bonded to the remainder of the molecule through a carbon orheteroatom. Exemplary heterocyclos include heteroaromatics such asfuranyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, orisoquinolinyl and the like. Exemplary substituents include one or moreof the following groups: hydrocarbyl, substituted hydrocarbyl, keto,hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy,aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals,esters and ethers.

The term “heteroaromatic” as used herein alone or as part of anothergroup denote optionally substituted aromatic groups having at least oneheteroatom in at least one ring, and preferably 5 or 6 atoms in eachring. The heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may bebonded to the remainder of the molecule through a carbon or heteroatom.Exemplary heteroaromatics include furyl, thienyl, pyridyl, oxazolyl,pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplarysubstituents include one or more of the following groups: hydrocarbyl,substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl,acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino,nitro, cyano, thiol, ketals, acetals, esters and ethers.

The term “acetamidyl” as used herein describes a chemical moietyrepresented by the formula NR₁C(O)R₂.

The term “carboxamido” as used herein, describes a chemical moietyrepresented by the formula C(O)NR₁R₂.

The term “alkoxycarbonyl” as used herein describes a chemical moietyrepresented by the formula C(O)OR.

The term “sulfonamido” as used herein describes a chemical moietyrepresented by the formula SO₂NR₁R₂.

The term “alkylsulfonyl” as used herein describes a chemical moietyrepresented by the formula SO₂R.

The term “sulfonamidy” as used herein describes a chemical moietyrepresented by the formula NRSO₂R.

As described herein for the terms “acetamidyl”, “carboxamido”,“alkocycarbonyl”, “sulfonamido”, “alkylsulfonyl”, and “sulfonamidyl”, R,R₁ and R₂ are independently hydrogen, alkyl, aryl, and arylakyl,optionally substituted with halogen, hydroxy or alkoxy.

DESCRIPTION OF THE PREFERRED EMBODIMENT

In one embodiment of the present invention, the compounds correspond toformula (1):

wherein:

-   -   X₁, X₂, X₃, X₄, X₅, and X₆ are each ring atoms defining a        6-membered heterocyclic ring;

X₁, X₃, and X₄ are independently carbon or nitrogen;

X₂, X₅, and X₆ are independently carbon, nitrogen, oxygen or sulfurwhere X₅ and X₆ are optionally substituted with a halogen, provided nomore than 4 of X₁, X₂, X₃, X₄, X₅, and X₆ are sp² hybridized;

L₁, L₃ and L₄ are linkages through which Z₁, Z₃, and Z₄, respectively,are covalently bonded to different ring atoms of the 6-memberedheterocyclic ring defined by X₁, X₂, X₃, X₄, X₅, and X₆, wherein Z₁ iscovalently bonded to X₁, Z₃ is covalently bonded to X₃, and Z₄ iscovalently bonded to X₄, each of L₁, L₃ and L₄ independently being acovalent bond or comprising one or more atoms through which Z₁, Z₃, andZ₄ are covalently bonded to X₁, X₃ and X₄, respectively;

Z₁ is hydrocarbyl or substituted hydrocarbyl;

Z₂ is hydrogen, an electron pair, or a hydrogen bond acceptor covalentlyor datively bonded to X₂;

Z₃ comprises a 5- or 6-membered heterocyclic or aromatic ringsubstituted with an amidine or a derivatized amidine group, the ringatoms of the 5- or 6-membered heterocyclic or aromatic ring of Z₃ beingcarbon, sulfur, nitrogen, or oxygen wherein the 5- or 6-membered ring isoptionally substituted at any position with halogen, hydroxy, haloalkyl,alkyl, carboxy, alkoxycarbonyl, or hydrocarbyloxy; and

Z₄ comprises a 5- or 6-membered heterocyclic or carbocyclic ring, thering atoms of the 5- or 6-membered heterocyclic or carbocyclic ring ofZ₄ being carbon, nitrogen, oxygen, or sulfur.

One aspect of the invention encompasses compounds corresponding toformula (1) wherein X₁, X₃, and X₄ are independently carbon or nitrogenand X₂, X₅, and X₆ are independently carbon, nitrogen, oxygen or sulfur.Typically, in this embodiment, no more than 4 of X₁, X₂, X₃, X₄, X₅, andX₆ are sp² hybridized. In one alternative of this embodiment, X₁, X₂,X₃, X₄, X₅, and X₆ are independently carbon or nitrogen, provided atleast one of X₁, X₂, X₃, X₄, X₅, and X₆ is nitrogen. In anotheralternative of this embodiment, X₃ is nitrogen, X₂ is carbon, and Z₂ ishydrogen, fluorine, oxygen, or sulfur. In yet another alternative ofthis embodiment, X₂ is nitrogen, oxygen or sulfur and Z₂ is hydrogen, anelectron pair, or a hydrogen bond acceptor. In yet another alternativeof this embodiment, X₂ is nitrogen and Z₂ is hydrogen, oxygen, amino, oracyl. In still another alternative of this embodiment, X₂ is carbon andX₃ is nitrogen. Still another alternative of this embodiment embracescompounds where at least one of X₁, X₂, X₃, X₄, X₅, and X₆ is carbon andthe carbon is sp³ hybridized. For each of the alternatives of thisembodiment, X₅ may be optionally substituted with a halogen. A preferredhalogen is chlorine. A more preferred halogen is fluorine.

In another aspect of compounds corresponding to formula (1), X₁, X₂, X₃,X₄, X₅, X₆, and Z₂ are as defined for compounds having formula (1) aboveand are selected to form the following 6-membered heterocyclic rings:piperidinone, dihydropyrimidinone, tetrahydropyrimidinone,dehydropiperidinedione, dihydropyridazinone, dihydroisoxazinone,tetrahydrotriazinedione, tetrahydrotriazinone, piperidine, andpiperazine. In one alternative of this embodiment, X₁, X₂, X₃, X₄, X₅,X₆, and Z₂ are selected to form a heterocyclic ring selected fromtetrahydrotriazinone, piperidinone, dihydropyrimidinone,tetrahydropyrimidinone, piperidine, and piperazine. In anotheralternative of this embodiment, X₁, X₂, X₃, X₄, X₅, X₆, and Z₂ areselected to form a heterocyclic ring selected from tetrahydrotriazinone,piperidinone, dihydropyrimidinone, and tetrahydropyrimidinone. In apreferred alternative of this embodiment, the heterocyclic ring definedby X₁, X₂, X₃, X₄, X₅, X₆, and Z₂ is tetrahydrotriazinone.

In one embodiment of compounds having formula (1), L₁ is X₉NH wherein X₉is covalently bonded to Z₁ and X₉ is a bond or (CH₂)_(m) wherein m is 1to 5. In one alternative of this embodiment (i.e., when L₁ is X₉NH), mis 1 to 2. In another alternative of this embodiment, L₁ is X₉NH whereinX₉ is covalently bonded to Z₁ and is a bond. In yet another alternativeof this embodiment, L₁ is a methylene or ethylene group. In anotheralternative of this embodiment, L₁ optionally contains a bond to X₆ toform a fused ring with the heterocyclic ring.

In one embodiment of compounds corresponding to formula (1), L₃ isselected from the group consisting of a glycine derivative, an alaninederivative, an amino derivative, and a sulfonyl derivative. In onealternative of this embodiment, L₃ is a glycine derivative. In anotheralternative of this embodiment, L₃ is CH₂CONHCH₂ where Z₃ is bonded tothe methylene bonded to the amine group.

In one embodiment of compounds corresponding to formula (1), L₄ isselected from the group consisting of a bond, methylene, ethylene, or anoptionally substituted heteroatom selected from nitrogen, oxygen, sulfurand phosphorus. In one alternative of this embodiment, L₄ is (CH₂)_(m)wherein m is 0 to 2. In a preferred alternative of this embodiment, L₄is a bond.

In one embodiment of compounds corresponding to formula (1), Z₁ ishydrocarbyl or substituted hydrocarbyl. In one alternative of thisembodiment (i.e., when Z₁ is hydrocarbyl or substituted hydrocarbyl), Z₁is optionally substituted C₂ to C₈ alkyl, optionally substituted C₃ toC₆ cycloalkyl and optionally substituted phenyl. In another alternativeof this embodiment, Z₁ is selected from the group consisting ofoptionally substituted cyclopropyl, isopropyl, cyclobutyl, isobutyl,sec-butyl, methyl, ethyl, and phenyl. In another alternative of thisembodiment, Z₁ is C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, thealkyl, alkenyl, or alkynyl being optionally substituted with fluorine,hydroxy, carboxy, or alkoxycarbonyl. In yet another alternative of thisembodiment, Z₁ is selected from the group consisting of cyclopropyl,isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl, sec-butyl,and phenyl optionally substituted at any substitutable position withfluorine, hydroxy, carboxy or alkoxycarbonyl. In yet another alternativeof this embodiment, Z₁ is propyl, isopropyl, cyclopropyl, tert-butyl andcyclobutyl. In another alternative of this embodiment, Z₁ is cyclopropylor isopropyl optionally substituted at any substitutable position withfluorine, hydroxy, carboxy or alkoxycarbonyl. In still anotheralternative of this embodiment, Z₁ is phenyl optionally substituted withfluorine, hydroxy, carboxy, or alkoxycarbonyl. In yet anotheralternative of this embodiment, Z₁ is trifluoroethyl or carboxymethyl.

In one embodiment of compounds corresponding to formula (1), Z₂ is ahydrogen bond acceptor. Generally, hydrogen bond acceptors areheteroatoms that have a lone pair of electrons available for hydrogenbonding. When taken with the carbon to which Z₂ is attached, suitablehydrogen bond acceptors are selected from the group consisting of C(O),C(S), C(Cl), C(Br), C(F), C(OH), COCH₃, COR, C(SH), CSR, and CNR₁R₂wherein R, R₁ and R₂ are independently hydrogen, alkyl, aryl, andarylakyl, optionally substituted with halogen, hydroxy or alkoxy.

In one embodiment of compounds corresponding to formula (1), Z₃ is a 5-or 6-membered heterocyclic or aromatic ring substituted with an amidineor a derivatized amidine group and may be optionally substituted at anysubstitutable position with halogen, hydroxy, haloalkyl, alkyl, carboxy,alkoxycarbonyl, or hydrocarbyloxy, or any combination thereof. Apreferred halogen is fluorine. In one alternative of this embodiment,directed toward the prodrugs of the compounds of formula (1), the 5- or6-membered heterocyclic or aromatic ring comprising Z₃ is substitutedwith a derivatized amidine which, upon hydrolysis, oxidation, reductionor elimination, or any combination thereof, yields an amidine group. Inanother alternative of this embodiment, Z₃ is a 6-membered carbocyclicaromatic ring substituted with either an amidine group, or forembodiments directed toward the prodrug, with a derivatized amidine. Inyet another embodiment, Z₃ comprises a substituted phenyl, thienyl, orfuranyl ring, the phenyl, thienyl or furanyl ring being substituted withan amidine or a derivatized amidine group, and optionally furthersubstituted at any substitutable position with fluorine, hydroxy,carboxy, alkoxycarbonyl, or hydrocarbyloxy. For embodiments directedtoward the prodrug, the amidine group is derivatized according to any ofthe embodiments described more thoroughly below. In yet anotheralternative of this embodiment, Z₃ corresponds to formula (a):

wherein

R₃₀₄ and R₃₀₆ are independently selected from the group consisting ofhydrogen, fluorine, hydroxy, carboxy, hydrocarbyloxy and alkoxycarbonyl;and

R₃₀₅ and R₃₀₇ are independently selected from the group consisting ofhydrogen, fluorine, methoxy, hydroxy and carboxy.

In one alternative of compounds wherein Z₃ corresponds to formula (a),Z₃ is selected from the group consisting of benzamidine-4-yl,3-hydroxybenzamidine-4-yl, 3,5-dihydroxybenzamidine-4-yl,2,5,6-trifluoro-3-hydroxybenzamidine-4-yl, 2-hydroxybenzamidine-4-yl and3,5,6-trifluoro-2-hydroxybenzamidine-4-yl.

In one embodiment of compounds corresponding to formula (1), Z₄comprises a 5- or 6-membered heterocyclic or carbocyclic ring, the ringatoms of the 5- or 6-membered heterocyclic or carbocyclic ring of Z₄being carbon, nitrogen, oxygen, or sulfur. In one alternative of thisembodiment, Z₄ comprises a 5- or 6-membered heterocyclic or carbocyclicring, the ring atoms of Z₄ being Z₄₀, Z₄₁, Z₄₂, Z₄₄ and Z₄₅ when Z₄ is a5-membered ring and Z₄₀, Z₄₁, Z₄₂, Z₄₃, Z₄₄ and Z₄₅ when Z₄ is a6-membered ring, Z₄₀, Z₄₁, Z₄₂, Z₄₃, Z₄₄ and Z₄₅, being carbon,nitrogen, oxygen or sulfur, Z₄₀ being the ring atom through which Z₄ isattached to the heterocyclic core ring, Z₄₁ and Z₄₅ each being in analpha position relative to Z₄₀, Z₄₂ and Z₄₄ each being in a betaposition relative to Z₄₀, Z₄₃ being in the gamma position relative toZ₄₀ when Z₄ is a 6-membered ring, Z₄ having a substituent R₄₂ covalentlyattached to Z₄₂, and a second substituent bonded to one of Z₄₁, Z₄₃,Z₄₄, or Z₄₅, the substituent being R₄₁ when bonded to Z₄₁, thesubstituent being R₄₃ when bonded to Z₄₃, the substituent being R₄₄ whenbonded to Z₄₄, and the substituent being R₄₅ when bonded to Z₄₅; R₄₂ isamino; and R₄₁, R₄₃, R₄₄ and R₄₅ are independently hydrogen,hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, or asubstituted or unsubstituted heteroatom selected from nitrogen, oxygen,sulfur and phosphorus, provided at least one of R₄₁, R₄₃, R₄₄ or R₄₅ isother than hydrogen. In another alternative of this embodiment, Z₄ is asubstituted, 6-membered, carbocyclic aromatic ring. In anotheralternative of this embodiment, Z₄ corresponds to formula (b):

wherein

R₄₂ is amino;

R₄₄ is hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen or asubstituted or unsubstituted heteroatom selected from nitrogen, oxygen,sulfur and phosphorus; and R₄₁, R₄₃ and R₄₅ are independently hydrogen,hydrocarbyl, substituted hydrocarbyl, halogen or an optionallysubstituted heteroatom selected from the group consisting of oxygen,nitrogen, and sulfur.

In one embodiment of compounds wherein Z₄ corresponds to formula (b),R₄₄ is hydrocarbyl, substituted hydrocarbyl, heteroaryl, heterocyclo,halogen, acetamido, guanidino, hydroxy, nitro, amino, amidosulfonyl,acylamido, hydrocarbyloxy, substituted hydrocarbyloxy, hydrocarbylthio,substituted hydrocarbylthio, hydrocarbylsulfonyl, or substitutedhydrocarbylsulfonyl. In one alternative of this embodiment, wherein Z₄corresponds to formula (b), R₄₄ is hydroxy, alkylsulfonyl, haloalkyl,carboxamidoalkyl, or carboxamidoalkylaryl. In another alternative ofthis embodiment, wherein Z₄ corresponds to formula (b), R₄₄ is selectedfrom the group consisting of hydrocarbyl, substituted hydrocarbyl,acetamidyl, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkoxy,haloalkythio, alkoxycarbonyl, carboxy, sulfonamido, carboxamido andsulfonamidyl, optionally substituted with fluorine. In still anotheralternative of this embodiment, R₄₄ is selected from the groupconsisting of hydroxy, carboxy, carboxamido, alkoxy, alkylsulfonyl,sulfonamido, and alkoxycarbonyl. In a preferred alternative of thisembodiment, R₄₄ is sec-butylamide, carboxy, ethoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isopropylamide or hydroxy. In yetanother alternative of this embodiment, each of R₄₁, R₄₃ and R₄₅ ishydrogen. In still yet another alternative of this embodiment, Z₄₁, Z₄₃or Z₄₅ is substituted with fluorine or chlorine. In another embodimentof this invention, R₄₄ is hydroxy, alkylsulfonyl, haloalkyl,carboxamidoalkyl, or carboxamidoalkylaryl.

In one alternative of compounds wherein Z₄ corresponds to formula (b),R₄₂ is amino; R₄₃ is hydrocarbyl, substituted hydrocarbyl, halogen or anoptionally substituted heteroatom selected from the group consisting ofoxygen, nitrogen, and sulfur; and R₄₁, R₄₄ and R₄₅ are independentlyhydrogen, halogen or alkoxy.

In another alternative of compounds wherein Z₄ corresponds to formula(b), R₄₂ is amino; R₄₅ is hydrocarbyl, substituted hydrocarbyl, halogenor an optionally substituted heteroatom selected from the groupconsisting of oxygen, nitrogen, and sulfur; and R₄₁, R₄₃ and R₄₄ areindependently hydrogen, halogen or alkoxy.

In yet another alternative of compounds wherein Z₄ corresponds toformula (b), R₄₂ is amino; R₄₁ is hydrocarbyl, substituted hydrocarbyl,halogen or an optionally substituted heteroatom selected from the groupconsisting of oxygen, nitrogen, and sulfur; and R₄₃, R₄₄ and R₄₅ areindependently hydrogen, halogen or alkoxy.

In an alternative embodiment of compounds of formula (1), Z₄ correspondsto formula (c)

wherein

Z₄₀, Z₄₁, Z₄₂, Z₄₄, and Z₄₅ are independently carbon, nitrogen, oxygenor sulfur, and R₄₁, R₄₂, R₄₄, and R₄₅ are as defined in connection withthe 6-membered carbocylic aromatic ring.

In another aspect of the invention, the compounds of formula (1) may berepresented by formula (2):

wherein X₁, X₂, X₃ X₄, X₅, X₆, Z₁, Z₂, Z₃, and Z₄ are as described forcompounds having structural formula (1) and X₉ is a direct bond or(CH₂)_(m) wherein m is 1 or 2. In one alternative of this embodiment,X₁, X₂, X₃, X₄, X₅, X₆, and Z₂ are selected to provide a piperidinone,dihydropyrimidinone, tetrahydropyrimidinone, dehydropiperidinedione,dihydropyridazinone, dihydroisoxazinone, tetrahydrotriazinedione,tetrahydrotriazinone, piperidine, and piperazine heterocyclic ring andZ₁, Z₂, Z₃, and Z₄ are as described for formula (1) and X₉ is a bond. Inanother alternative of this embodiment, X₁, X₂, X₃, X₄, X₅, X₆ and Z₂are selected to provide a heterocyclic ring selected fromtetrahydrotriazinone, piperidinone, dihydropyrimidinone,tetrahydropyrimidinone, piperidine, and piperazine. In yet anotheralternative of this embodiment, X₁, X₂, X₃, X₄, X₅, X₆ and Z₂ areselected to provide a heterocyclic ring selected fromtetrahydrotriazinone, piperidinone, dihydropyrimidinone, andtetrahydropyrimidinone. In a preferred alternative of this embodiment,the heterocyclic ring defined by X₁, X₂, X₃, X₄, X₅, X₆ and Z₂ istetrahydrotriazinone.

In a preferred embodiment of compounds corresponding to formula (2), X₉is a bond; Z₁ is selected from the group consisting of cyclopropyl,methyl, ethyl, isobutyl, tert-butyl, and sec-butyl optionallysubstituted at any substitutable position with fluorine, hydroxy,carboxy, or alkoxycarbonyl; Z₃ corresponds to formula (a) and isoptionally substituted at any substitutable position with fluorine,hydroxy, carboxy, or hydrocarbyloxy; Z₄ corresponds to formula (b)wherein R₄₂ is amino and R₄₄ is selected from the group consisting ofhydrocarbyl, substituted hydrocarbyl, acetamidyl, alkoxy, hydroxy,amino, alkylsulfonyl, haloalkoxy, haloalkythio, alkoxycarbonyl, carboxy,sulfonamido, carboxamido and sulfonamidyl, optionally substituted withfluorine; and X₁, X₂, X₃, X₄, X₅, X₆ and Z₂ are as defined above forcompounds having formula (1).

In a preferred embodiment, compounds corresponding to formula (2) may berepresented by formula (2-a):

wherein

X₁, X₄, X₅ and X₆ are independently carbon or nitrogen;

Z₁ is selected from the group consisting of cyclopropyl, isopropyl,methyl, ethyl, cyclobutyl, isobutyl, tert-butyl, sec-butyl, and phenyloptionally substituted with fluorine, hydroxy, carboxy, oralkoxycarbonyl;

R₄₄₀ is C₁-C₆ alkyl, aryl, aralkyl, carboxy, or carboxyalkyl, whereinsaid alkyl, aryl, aralkyl, carboxy, or carboxyalkyl is optionallyfurther substituted by fluorine; and

R₃₁₀ and R₃₁₁ are independently selected from the group consisting ofhydrogen, fluorine, hydroxy, alkoxy, and carboxy.

In another preferred embodiment, compounds corresponding to formula (2)may be represented by formula (2-b):

wherein

X₁, X₄, X₅ and X₆ are independently carbon or nitrogen;

Z₁ is selected from the group consisting of cyclopropyl, isopropyl,methyl, ethyl, cyclobutyl, isobutyl, tert-butyl, sec-butyl, and phenyloptionally substituted with fluorine, hydroxy, carboxy, oralkoxycarbonyl;

R₄₄₀ is C₁-C₆ alkyl, aryl, aralkyl, carboxy, or carboxyalkyl, whereinsaid alkyl, aryl, aralkyl, carboxy, or carboxyalkyl is optionallyfurther substituted by fluorine; and

R₃₁₀ and R₃₁₁ are independently selected from the group consisting ofhydrogen, fluorine, hydroxy, alkoxy, and carboxy.

In a preferred alternative of compounds corresponding to formula (2),the compounds possess a tetrahydrotriazinone heterocyclic ring havingformula (2-c):

wherein:

Z₁, Z₂, and Z₃ are as defined for compounds having either of formula (1)and formula (2) above.

In one alternative of this embodiment (i.e., compounds having atetrahydrotriazinone heterocyclic ring core), Z₁ is optionallysubstituted C₂ to C₈ alkyl, optionally substituted C₃ to C₆ cycloalkyland optionally substituted phenyl. Preferred Z₁ substituents areoptionally substituted cyclopropyl, isopropyl, cyclobutyl, methyl, ethyland phenyl. In another alternative of this embodiment, Z₄ is asubstituted, 6-membered, heterocyclic or carbocyclic aromatic ring.

Another aspect of the invention embraces compounds which correspond toformula (1) having the following fused ring formula (3):

wherein

Z₁, Z₂, Z₃, Z₄, L₃, X₁, X₂, X₃, X₄, and X₅ are as defined for compoundshaving formula (1) or (2) above;

X₆ is carbon or nitrogen;

X₇ and X₈ are independently carbon, nitrogen, oxygen or sulfur;

R₇₀ and R₈₀ are independently selected from the group consisting ofhydrogen, halogen, amino, hydrocarbyl, substituted hydrocarbyl, aryl,wherein aryl is phenyl optionally substituted by hydroxy, amino, C₁-C₈alkyl, or halogen provided that R₇₀ is not present when X₇ is a bond andR₈₀ is not present when X₈ is a bond; or R₇₀ and R₈₀, along with thering atoms to which each is attached, form a 5- or 6-membered saturatedring; and

n is 0 to 2.

In a preferred embodiment of compounds of formula (3), L₃ is CH₂CONHCH₂.In one alternative of this embodiment, (i.e., when L₃ is CH₂CONHCH₂), X₇and X₈ are carbon. In another alternative of this embodiment, Z₃corresponds to formula (a) and Z₄ corresponds to formula (b).

In another aspect of this invention, compounds corresponding to any offormulas (1), (2), or (3) possess a hydroxy or carboxy substituent atany one of Z₁, Z₂ or Z₃.

In another aspect of this invention for compounds corresponding to anyof formulas (1), (2), or (3), Z₃ is —R₃₀₀C(═NR₃₀₁)NR₃₀₂R₃₀₃, whereinR₃₀₀ is a 6-membered carbocyclic aromatic ring, R₃₀₁, R₃₀₂, R₃₀₃ areindependently selected from the group consisting of hydrogen, halogen,optionally substituted hydrocarbyl, and an optionally substitutedheteroatom selected from the group consisting of oxygen, nitrogen,phosphorus and sulfur, provided at least one of R₃₀₁, R₃₀₂, R₃₀₃ isother than hydrogen. In yet another alternative of this embodiment, Z₃is —R₃₀₀C(═NR₃₀₁)NR₃₀₂R₃₀₃, wherein R₃₀₀ is a 6-membered carbocyclicaromatic ring, and at least two of R₃₀₁, R₃₀₂, R₃₀₃ are ring atoms of aheterocyclic ring. In an alternative of this embodiment, Z₃ is—R₃₀₀C(═NR₃₀₁)NR₃₀₂R₃₀₃, wherein R₃₀₀ is a 6-membered carbocyclicaromatic ring, and at least one of R₃₀₁, R₃₀₂, R₃₀₃ are ring atoms of aheterocyclic ring fused to R₃₀₀.

In yet another aspect of this invention for compounds corresponding toany of formulas (1), (2), or (3), Z₃ is a benzamidine derivatized withone or more groups selected from carbonyl, thiocarbonyl, imino, enamino,phosphorus, and sulfur, where the benzamidine derivative hydrolyzesunder physiological conditions to form benzamidine. In a furtherembodiment, Z₃ is a benzamidine derivatized with one or more groupsselected from optionally substituted hydrocarbyl, provided that thecarbon atom directly bonded to the amidine is sp³ hybridized and aryl,where the benzamidine derivative is oxidized under physiologicalconditions to form benzamidine. In yet another embodiment, Z₃ is abenzamidine derivatized with one or more heteroatoms selected fromoxygen, nitrogen in its most reduced state, and sulfur in its mostreduced state, where the benzamidine derivative is reduced underphysiological conditions to form benzamidine. In still anotherembodiment, Z₃ is a benzamidine derivatized with one or moresubstituents selected from a hydrocarbyl substituted at the beta carbonwith carbonyl, sulfonyl, sulfinyl, cyano, nitro and an alkyl, aryl, orheterocyclic group substituted with oxygen, nitrogen, or sulfur at thecarbon directly bonded to the amidine group, where the benzamidinederivative undergoes elimination at physiological conditions to formbenzamidine.

In a further embodiment for compounds corresponding to any of formulas(1), (2), or (3), Z₃ corresponds to formula (d):

wherein:

R₃₀₁, R₃₀₂, and R₃₀₃ are independently selected from the groupconsisting of:

(i) hydrogen, —C(═O)R_(a), —C(═O)OR_(a), —S(═O)OR_(a), —S(═O)SR_(a),—S(═O)₂OR_(a), —S(═O)₂SR_(a) and alkenyl, wherein R_(a) is selected fromthe group consisting of hydrocarbyl, substituted hydrocarbyl, andheterocylo, provided, however, that the carbon atom of R₃₀₁, R₃₀₂, andR₃₀₃ directly bonded to the amidine is sp² hybridized when R₃₀₁, R₃₀₂,and R₃₀₃ is alkenyl,

(ii) hydrogen, optionally substituted hydrocarbyl and aryl, provided,however, the carbon atom of R₃₀₁, R₃₀₂, and R₃₀₃ directly bonded to theamidine is sp³ hybridized when R₃₀₁, R₃₀₂, and R₃₀₃ is optionallysubstituted hydrocarbyl,

(iii) hydrogen, —OR_(b), —SR_(b), —NR_(b), or —N(R_(b))₂, wherein eachR_(b) is independently optionally substituted hydrocarbyl, andheterocylo, and

(iv) hydrogen, substituted hydrocarbyl wherein the carbon bonded to theamidine group is substituted with —OR_(c), —SR_(c), —NR_(c), or—N(R_(c))₂, wherein each R_(c) is independently —C(O)R_(d), —C(O)NR_(d),—C(O)OR_(d), —C(O)N(Rd)₂ and each R_(d) is independently hydrocarbyl,substituted hydrocarbyl or heterocyclo, and substituted alkyl with thecarbon atom beta to the point of attachment to the amidine group beingan unsaturated electron withdrawing group, provided, however, at leastone of R₃₀₁, R₃₀₂, and R₃₀₃ is other than hydrogen;

R₃₀₄ is selected from the group consisting of halogen, hydrogen,hydroxyl, alkyl, sulfhydryl, alkoxy, and alkylthio;

R₃₀₅ is selected from the group consisting of oxygen, sulfur, halogen,hydrogen, hydroxyl, alkyl, sulfhydryl, alkoxy, and alkylthio;

R₃₀₆ is selected from the group consisting of halogen, hydrogen,hydroxyl, alkyl, sulfhydryl, alkoxy, and alkylthio; and

R₃₀₇ is selected from the group consisting of oxygen, sulfur, halogen,hydrogen, hydroxyl, alkyl, sulfhydryl, alkoxy, and alkylthio.

In one embodiment, the benzamidine derivative is hydrolyzed underphysiological conditions to form benzamidine when Z₃ is a benzamidinederivative having formula (d) and R₃₀₁, R₃₀₂, and R₃₀₃ are independentlyselected from hydrogen, —C(═O)R_(a), —C(═O)OR_(a), —S(═O)OR_(a),—S(═O)SR_(a), —S(═O)₂OR_(a), —S(═O)₂SR_(a) and alkenyl, wherein R_(a) isselected from the group consisting of hydrocarbyl, substitutedhydrocarbyl, and heterocylo, provided, however, that the carbon atom ofR₃₀₁, R₃₀₂, and R₃₀₃ directly bonded to the amidine is sp² hybridizedwhen R₃₀₁, R₃₀₂, and R₃₀₃ is alkenyl.

In a further embodiment, the benzamidine derivative is oxidized underphysiological conditions to form benzamidine when Z₃ is a benzamidinederivative having formula (d) and R₃₀₁, R₃₀₂, and R₃₀₃ are independentlyselected from hydrogen, optionally substituted hydrocarbyl and aryl,provided, however, the carbon atom of R₃₀₁, R₃₀₂, and R₃₀₃ directlybonded to the amidine is Sp³ hybridized when R₃₀₁, R₃₀₂, and R₃₀₃ isoptionally substituted hydrocarbyl.

In still another embodiment, the benzamidine derivative is reduced underphysiological conditions to form benzamidine when Z₃ is a benzamidinederivative having formula (d) and R₃₀₁, R₃₀₂, and R₃₀₃ are independentlyselected from hydrogen, —OR_(b), —SR_(b), —NR_(b), or —N(R_(b))₂,wherein each R_(b) is independently optionally substituted hydrocarbyl,and heterocylo.

In an alternative embodiment, the benzamidine derivative undergoeselimination at physiological conditions to form benzamidine when Z₃ is abenzamidine derivative having formula (d) and R₃₀₁, R₃₀₂, and R₃₀₃ areindependently selected from hydrogen, substituted hydrocarbyl whereinthe carbon bonded to the amidine group is substituted with —OR_(c),—SR_(c), —NR_(c), or —N(R_(c))₂, wherein each R_(c) is independently—C(O)R_(d), —C(O)NR_(d), —C(O)OR_(d), —C(O)N(R_(d))₂ and each R_(d) isindependently hydrocarbyl, substituted hydrocarbyl or heterocyclo, andsubstituted alkyl with the carbon atom beta to the point of attachmentto the amidine group being an unsaturated electron withdrawing group.

Another aspect of the invention embraces intermediate compounds havingeither of two formulae. Compounds corresponding to one of the formulaemay be represented by formula (4):

wherein

X₁, X₂, X₅, and X₆ are members of a heterocyclic ring;

X₁, X₂ and X₃ are independently carbon or nitrogen;

X₅ and X₆ are independently selected from the group consisting ofnitrogen, oxygen, sulfur, carbon, C(F) and C(Br);

provided no more than 4 of X₁, X₂, X₃, X₄, X₅, and X₆ are sp²hybridized;

Z₁ is hydrocarbyl, or substituted hydrocarbyl;

Z₂ is a hydrogen bond acceptor covalently or datively bonded to X₂;

T₃ is selected from the group consisting of hydroxy, alkoxy, substitutedalkoxy, and substituted amino; and

T₄ is selected from the group consisting of —Cl, —Br, —I, —S(CH₃), and—OSO₂(CF₃).

Intermediate compounds represented by the other formula correspond toformula (5):

wherein

X₁, X₂, X₅, and X₆ are members of a heterocyclic ring;

X₁, X₂ and X₃ are independently carbon or nitrogen;

X₅ and X₆ are independently selected from the group consisting ofnitrogen, oxygen, sulfur, carbon, C(F) and C(Br);

provided no more than 4 of X₁, X₂, X₃, X₄, X₅, and X₆ are sp²hybridized;

Z₁ is hydrocarbyl, or substituted hydrocarbyl;

Z₂ is a hydrogen bond acceptor covalently or datively bonded to X₂; and

Z₄ comprises hydrocarbyl, substituted hydrocarbyl or a 5- or 6-memberedheterocyclic or carbocyclic ring, the ring atoms of the 5 or 6 memberedheterocyclic or carboxylic ring of Z₄ being carbon, nitrogen, oxygen, orsulfur.

Among the preferred embodiments, therefore, are compounds correspondingto any one of formulas (1), (2), or (3) wherein X₉ is a direct bond, Z₄is a substituted, 6-membered, carbocyclic aromatic ring, Z₃ is benzenesubstituted with an amidine or a derivatized amidine group which, uponhydrolysis, oxidation, reduction or elimination under physiologicalconditions yields an amidine group, and Z₁ is selected from the groupconsisting of cyclopropyl, isopropyl, methyl, cyclobutyl,trifluoroethyl, carboxymethyl and phenyl. In an alternative of thisembodiment, Z₄ is phenyl substituted with two substituents, R₄₂ and R₄₄wherein R₄₂ and R₄₄ are as described for any of formulas (1), (2), or(3).

Following the processes described in the Schemes, Examples or elsewhereherein, compounds corresponding to each of formulae A, B, C, and D andhaving any of the combinations of substituents identified in Table 1 maybe prepared.

wherein X₁, X₂, X₃, X₄, X₅, and X₆ are selected to provide the followingheterocyclic rings: piperidinone, dihydropyrimidinone,tetrahydropyrimidinone, dehydropiperidinedione, dihydropyridazinone,dihydroisoxazinone, tetrahydrotriazinedione, tetrahydrotriazinone,piperidine, and piperazine and, for structure (C), one of Z₄₁ and Z₄₅ issulfur while the other is carbon and, for structure (D), one of Z₄₁ andZ₄₅ is nitrogen while the other is carbon. As employed herein, unlessotherwise indicated, “core” refers to the 6-membered ring to which Z₁,Z₃ and Z₄, through their respective linkages, are attached.

TABLE 1 Core Z₁ R₄₄ Piperidinone substituted hydroxy alkyl Piperidinonesubstituted isobutylsulfonyl alkyl Piperidinone substitutedtrifluoromethyl alkyl Piperidinone substituted carboxamidobenzyl alkylPiperidinone substituted carboxamidobutyl-2-yl alkyl Piperidinonesubstituted isobutyramido alkyl Piperidinone substituted isobutoxy alkylPiperidinone substituted carboethoxy alkyl Piperidinone substitutedcarboxyl alkyl Piperidinone substituted amino alkyl Dihydropyrimidinonesubstituted hydroxy alkyl Dihydropyrimidinone substitutedisobutylsulfonyl alkyl Dihydropyrimidinone substituted trifluoromethylalkyl Dihydropyrimidinone substituted carboxamidobenzyl alkylDihydropyrimidinone substituted carboxamidobutyl-2-yl alkylDihydropyrimidinone substituted isobutyramido alkyl Dihydropyrimidinonesubstituted isobutoxy alkyl Dihydropyrimidinone substituted carboethoxyalkyl Dihydropyrimidinone substituted carboxyl alkyl Dihydropyrimidinonesubstituted amino alkyl Tetrahydropyrimidinone substituted hydroxy alkylTetrahydropyrimidinone substituted isobutylsulfonyl alkylTetrahydropyrimidinone substituted trifluoromethyl alkylTetrahydropyrimidinone substituted carboxamidobenzyl alkylTetrahydropyrimidinone substituted carboxamidobutyl-2-yl alkylTetrahydropyrimidinone substituted isobutyramido alkylTetrahydropyrimidinone substituted isobutoxy alkylTetrahydropyrimidinone substituted carboethoxy alkylTetrahydropyrimidinone substituted carboxyl alkyl Tetrahydropyrimidinonesubstituted amino alkyl Dehydropiperidinedione substituted hydroxy alkylDehydropiperidinedione substituted isobutylsulfonyl alkylDehydropiperidinedione substituted trifluoromethyl alkylDehydropiperidinedione substituted carboxamidobenzyl alkylDehydropiperidinedione substituted carboxamidobutyl-2-yl alkylDehydropiperidinedione substituted isobutyramido alkylDehydropiperidinedione substituted isobutoxy alkylDehydropiperidinedione substituted carboethoxy alkylDehydropiperidinedione substituted carboxyl alkyl Dehydropiperidinedionesubstituted amino alkyl Dihydropyridazinone substituted hydroxy alkylDihydropyridazinone substituted isobutylsulfonyl alkylDihydropyridazinone substituted trifluoromethyl alkylDihydropyridazinone substituted carboxamidobenzyl alkylDihydropyridazinone substituted carboxamidobutyl-2-yl alkylDihydropyridazinone substituted isobutyramido alkyl Dihydropyridazinonesubstituted isobutoxy alkyl Dihydropyridazinone substituted carboethoxyalkyl Dihydropyridazinone substituted carboxyl alkyl Dihydropyridazinonesubstituted amino alkyl Dihydroisoxazinone substituted hydroxy alkylDihydroisoxazinone substituted isobutylsulfonyl alkyl Dihydroisoxazinonesubstituted trifluoromethyl alkyl Dihydroisoxazinone substitutedcarboxamidobenzyl alkyl Dihydroisoxazinone substitutedcarboxamidobutyl-2-yl alkyl Dihydroisoxazinone substituted isobutyramidoalkyl Dihydroisoxazinone substituted isobutoxy alkyl Dihydroisoxazinonesubstituted carboethoxy alkyl Dihydroisoxazinone substituted carboxylalkyl Dihydroisoxazinone substituted amino alkyl Tetrahydrotriazinedionesubstituted hydroxy alkyl Tetrahydrotriazinedione substitutedisobutylsulfonyl alkyl Tetrahydrotriazinedione substitutedtrifluoromethyl alkyl Tetrahydrotriazinedione substitutedcarboxamidobenzyl alkyl Tetrahydrotriazinedione substitutedcarboxamidobutyl-2-yl alkyl Tetrahydrotriazinedione substitutedisobutyramido alkyl Tetrahydrotriazinedione substituted isobutoxy alkylTetrahydrotriazinedione substituted carboethoxy alkylTetrahydrotriazinedione substituted carboxyl alkylTetrahydrotriazinedione substituted amino alkyl Tetrahydrotriazinonesubstituted hydroxy alkyl Tetrahydrotriazinone substitutedisobutylsulfonyl alkyl Tetrahydrotriazinone substituted trifluoromethylalkyl Tetrahydrotriazinone substituted carboxamidobenzyl alkylTetrahydrotriazinone substituted carboxamidobutyl-2-yl alkylTetrahydrotriazinone substituted isobutyramido alkylTetrahydrotriazinone substituted isobutoxy alkyl Tetrahydrotriazinonesubstituted carboethoxy alkyl Tetrahydrotriazinone substituted carboxylalkyl Tetrahydrotriazinone substituted amino alkyl Piperidinesubstituted hydroxy alkyl Piperidine substituted isobutylsulfonyl alkylPiperidine substituted trifluoromethyl alkyl Piperidine substitutedcarboxamidobenzyl alkyl Piperidine substituted carboxamidobutyl-2-ylalkyl Piperidine substituted isobutyramido alkyl Piperidine substitutedisobutoxy alkyl Piperidine substituted carboethoxy alkyl Piperidinesubstituted carboxyl alkyl Piperidine substituted amino alkyl Piperazinesubstituted hydroxy alkyl Piperazine substituted isobutylsulfonyl alkylPiperazine substituted trifluoromethyl alkyl Piperazine substitutedcarboxamidobenzyl alkyl Piperazine substituted carboxamidobutyl-2-ylalkyl Piperazine substituted isobutyramido alkyl Piperazine substitutedisobutoxy alkyl Piperazine substituted carboethoxy alkyl Piperazinesubstituted carboxyl alkyl Piperazine substituted amino alkylPiperidinone alkyl hydroxy Piperidinone alkyl isobutylsulfonylPiperidinone alkyl trifluoromethyl Piperidinone alkyl carboxamidobenzylPiperidinone alkyl carboxamidobutyl-2-yl Piperidinone alkylisobutyramido Piperidinone alkyl isobutoxy Piperidinone alkylcarboethoxy Piperidinone alkyl carboxyl Piperidinone alkyl aminoDihydropyrimidinone alkyl hydroxy Dihydropyrimidinone alkylisobutylsulfonyl Dihydropyrimidinone alkyl trifluoromethylDihydropyrimidinone alkyl carboxamidobenzyl Dihydropyrimidinone alkylcarboxamidobutyl-2-yl Dihydropyrimidinone alkyl isobutyramidoDihydropyrimidinone alkyl isobutoxy Dihydropyrimidinone alkylcarboethoxy Dihydropyrimidinone alkyl carboxyl Dihydropyrimidinone alkylamino Tetrahydropyrimidinone alkyl hydroxy Tetrahydropyrimidinone alkylisobutylsulfonyl Tetrahydropyrimidinone alkyl trifluoromethylTetrahydropyrimidinone alkyl carboxamidobenzyl Tetrahydropyrimidinonealkyl carboxamidobutyl-2-yl Tetrahydropyrimidinone alkyl isobutyramidoTetrahydropyrimidinone alkyl isobutoxy Tetrahydropyrimidinone alkylcarboethoxy Tetrahydropyrimidinone alkyl carboxyl Tetrahydropyrimidinonealkyl amino Dehydropiperidinedione alkyl hydroxy Dehydropiperidinedionealkyl isobutylsulfonyl Dehydropiperidinedione alkyl trifluoromethylDehydropiperidinedione alkyl carboxamidobenzyl Dehydropiperidinedionealkyl carboxamidobutyl-2-yl Dehydropiperidinedione alkyl isobutyramidoDehydropiperidinedione alkyl isobutoxy Dehydropiperidinedione alkylcarboethoxy Dehydropiperidinedione alkyl carboxyl Dehydropiperidinedionealkyl amino Dihydropyridazinone alkyl hydroxy Dihydropyridazinone alkylisobutylsulfonyl Dihydropyridazinone alkyl trifluoromethylDihydropyridazinone alkyl carboxamidobenzyl Dihydropyridazinone alkylcarboxamidobutyl-2-yl Dihydropyridazinone alkyl isobutyramidoDihydropyridazinone alkyl isobutoxy Dihydropyridazinone alkylcarboethoxy Dihydropyridazinone alkyl carboxyl Dihydropyridazinone alkylamino Dihydroisoxazinone alkyl hydroxy Dihydroisoxazinone alkylisobutylsulfonyl Dihydroisoxazinone alkyl trifluoromethylDihydroisoxazinone alkyl carboxamidobenzyl Dihydroisoxazinone alkylcarboxamidobutyl-2-yl Dihydroisoxazinone alkyl isobutyramidoDihydroisoxazinone alkyl isobutoxy Dihydroisoxazinone alkyl carboethoxyDihydroisoxazinone alkyl carboxyl Dihydroisoxazinone alkyl aminoTetrahydrotriazinedione alkyl hydroxy Tetrahydrotriazinedione alkylisobutylsulfonyl Tetrahydrotriazinedione alkyl trifluoromethylTetrahydrotriazinedione alkyl carboxamidobenzyl Tetrahydrotriazinedionealkyl carboxamidobutyl-2-yl Tetrahydrotriazinedione alkyl isobutyramidoTetrahydrotriazinedione alkyl isobutoxy Tetrahydrotriazinedione alkylcarboethoxy Tetrahydrotriazinedione alkyl carboxylTetrahydrotriazinedione alkyl amino Tetrahydrotriazinone alkyl hydroxyTetrahydrotriazinone alkyl isobutylsulfonyl Tetrahydrotriazinone alkyltrifluoromethyl Tetrahydrotriazinone alkyl carboxamidobenzylTetrahydrotriazinone alkyl carboxamidobutyl-2-yl Tetrahydrotriazinonealkyl isobutyramido Tetrahydrotriazinone alkyl isobutoxyTetrahydrotriazinone alkyl carboethoxy Tetrahydrotriazinone alkylcarboxyl Tetrahydrotriazinone alkyl amino Piperidine alkyl hydroxyPiperidine alkyl isobutylsulfonyl Piperidine alkyl trifluoromethylPiperidine alkyl carboxamidobenzyl Piperidine alkylcarboxamidobutyl-2-yl Piperidine alkyl isobutyramido Piperidine alkylisobutoxy Piperidine alkyl carboethoxy Piperidine alkyl carboxylPiperidine alkyl amino Piperazine alkyl hydroxy Piperazine alkylisobutylsulfonyl Piperazine alkyl trifluoromethyl Piperazine alkylcarboxamidobenzyl Piperazine alkyl carboxamidobutyl-2-yl Piperazinealkyl isobutyramido Piperazine alkyl isobutoxy Piperazine alkylcarboethoxy Piperazine alkyl carboxyl Piperazine alkyl aminoPiperidinone substituted hydroxy phenyl Piperidinone substitutedisobutylsulfonyl phenyl Piperidinone substituted trifluoromethyl phenylPiperidinone substituted carboxamidobenzyl phenyl Piperidinonesubstituted carboxamidobutyl-2-yl phenyl Piperidinone substitutedisobutyramido phenyl Piperidinone substituted isobutoxy phenylPiperidinone substituted carboethoxy phenyl Piperidinone substitutedcarboxyl phenyl Piperidinone substituted amino phenylDihydropyrimidinone substituted hydroxy phenyl Dihydropyrimidinonesubstituted isobutylsulfonyl phenyl Dihydropyrimidinone substitutedtrifluoromethyl phenyl Dihydropyrimidinone substituted carboxamidobenzylphenyl Dihydropyrimidinone substituted carboxamidobutyl-2-yl phenylDihydropyrimidinone substituted isobutyramido phenyl Dihydropyrimidinonesubstituted isobutoxy phenyl Dihydropyrimidinone substituted carboethoxyphenyl Dihydropyrimidinone substituted carboxyl phenylDihydropyrimidinone substituted amino phenyl Tetrahydropyrimidinonesubstituted hydroxy phenyl Tetrahydropyrimidinone substitutedisobutylsulfonyl phenyl Tetrahydropyrimidinone substitutedtrifluoromethyl phenyl Tetrahydropyrimidinone substitutedcarboxamidobenzyl phenyl Tetrahydropyrimidinone substitutedcarboxamidobutyl-2-yl phenyl Tetrahydropyrimidinone substitutedisobutyramido phenyl Tetrahydropyrimidinone substituted isobutoxy phenylTetrahydropyrimidinone substituted carboethoxy phenylTetrahydropyrimidinone substituted carboxyl phenylTetrahydropyrimidinone substituted amino phenyl Dehydropiperidinedionesubstituted hydroxy phenyl Dehydropiperidinedione substitutedisobutylsulfonyl phenyl Dehydropiperidinedione substitutedtrifluoromethyl phenyl Dehydropiperidinedione substitutedcarboxamidobenzyl phenyl Dehydropiperidinedione substitutedcarboxamidobutyl-2-yl phenyl Dehydropiperidinedione substitutedisobutyramido phenyl Dehydropiperidinedione substituted isobutoxy phenylDehydropiperidinedione substituted carboethoxy phenylDehydropiperidinedione substituted carboxyl phenylDehydropiperidinedione substituted amino phenyl Dihydropyridazinonesubstituted hydroxy phenyl Dihydropyridazinone substitutedisobutylsulfonyl phenyl Dihydropyridazinone substituted trifluoromethylphenyl Dihydropyridazinone substituted carboxamidobenzyl phenylDihydropyridazinone substituted carboxamidobutyl-2-yl phenylDihydropyridazinone substituted isobutyramido phenyl Dihydropyridazinonesubstituted isobutoxy phenyl Dihydropyridazinone substituted carboethoxyphenyl Dihydropyridazinone substituted carboxyl phenylDihydropyridazinone substituted amino phenyl Dihydroisoxazinonesubstituted hydroxy phenyl Dihydroisoxazinone substitutedisobutylsulfonyl phenyl Dihydroisoxazinone substituted trifluoromethylphenyl Dihydroisoxazinone substituted carboxamidobenzyl phenylDihydroisoxazinone substituted carboxamidobutyl-2-yl phenylDihydroisoxazinone substituted isobutyramido phenyl Dihydroisoxazinonesubstituted isobutoxy phenyl Dihydroisoxazinone substituted carboethoxyphenyl Dihydroisoxazinone substituted carboxyl phenyl Dihydroisoxazinonesubstituted amino phenyl Tetrahydrotriazinedione substituted hydroxyphenyl Tetrahydrotriazinedione substituted isobutylsulfonyl phenylTetrahydrotriazinedione substituted trifluoromethyl phenylTetrahydrotriazinedione substituted carboxamidobenzyl phenylTetrahydrotriazinedione substituted carboxamidobutyl-2-yl phenylTetrahydrotriazinedione substituted isobutyramido phenylTetrahydrotriazinedione substituted isobutoxy phenylTetrahydrotriazinedione substituted carboethoxy phenylTetrahydrotriazinedione substituted carboxyl phenylTetrahydrotriazinedione substituted amino phenyl Tetrahydrotriazinonesubstituted hydroxy phenyl Tetrahydrotriazinone substitutedisobutylsulfonyl phenyl Tetrahydrotriazinone substituted trifluoromethylphenyl Tetrahydrotriazinone substituted carboxamidobenzyl phenylTetrahydrotriazinone substituted carboxamidobutyl-2-yl phenylTetrahydrotriazinone substituted isobutyramido phenylTetrahydrotriazinone substituted isobutoxy phenyl Tetrahydrotriazinonesubstituted carboethoxy phenyl Tetrahydrotriazinone substituted carboxylphenyl Tetrahydrotriazinone substituted amino phenyl Piperidinesubstituted hydroxy phenyl Piperidine substituted isobutylsulfonylphenyl Piperidine substituted trifluoromethyl phenyl Piperidinesubstituted carboxamidobenzyl phenyl Piperidine substitutedcarboxamidobutyl-2-yl phenyl Piperidine substituted isobutyramido phenylPiperidine substituted isobutoxy phenyl Piperidine substitutedcarboethoxy phenyl Piperidine substituted carboxyl phenyl Piperidinesubstituted amino phenyl Piperazine substituted hydroxy phenylPiperazine substituted isobutylsulfonyl phenyl Piperazine substitutedtrifluoromethyl phenyl Piperazine substituted carboxamidobenzyl phenylPiperazine substituted carboxamidobutyl-2-yl phenyl Piperazinesubstituted isobutyramido phenyl Piperazine substituted isobutoxy phenylPiperazine substituted carboethoxy phenyl Piperazine substitutedcarboxyl phenyl Piperazine substituted amino phenyl Piperidinone phenylhydroxy Piperidinone phenyl isobutylsulfonyl Piperidinone phenyltrifluoromethyl Piperidinone phenyl carboxamidobenzyl Piperidinonephenyl carboxamidobutyl-2-yl Piperidinone phenyl isobutyramidoPiperidinone phenyl isobutoxy Piperidinone phenyl carboethoxyPiperidinone phenyl carboxyl Piperidinone phenyl aminoDihydropyrimidinone phenyl hydroxy Dihydropyrimidinone phenylisobutylsulfonyl Dihydropyrimidinone phenyl trifluoromethylDihydropyrimidinone phenyl carboxamidobenzyl Dihydropyrimidinone phenylcarboxamidobutyl-2-yl Dihydropyrimidinone phenyl isobutyramidoDihydropyrimidinone phenyl isobutoxy Dihydropyrimidinone phenylcarboethoxy Dihydropyrimidinone phenyl carboxyl Dihydropyrimidinonephenyl amino Tetrahydropyrimidinone phenyl hydroxyTetrahydropyrimidinone phenyl isobutylsulfonyl Tetrahydropyrimidinonephenyl trifluoromethyl Tetrahydropyrimidinone phenyl carboxamidobenzylTetrahydropyrimidinone phenyl carboxamidobutyl-2-ylTetrahydropyrimidinone phenyl isobutyramido Tetrahydropyrimidinonephenyl isobutoxy Tetrahydropyrimidinone phenyl carboethoxyTetrahydropyrimidinone phenyl carboxyl Tetrahydropyrimidinone phenylamino Dehydropiperidinedione phenyl hydroxy Dehydropiperidinedionephenyl isobutylsulfonyl Dehydropiperidinedione phenyl trifluoromethylDehydropiperidinedione phenyl carboxamidobenzyl Dehydropiperidinedionephenyl carboxamidobutyl-2-yl Dehydropiperidinedione phenyl isobutyramidoDehydropiperidinedione phenyl isobutoxy Dehydropiperidinedione phenylcarboethoxy Dehydropiperidinedione phenyl carboxylDehydropiperidinedione phenyl amino Dihydropyridazinone phenyl hydroxyDihydropyridazinone phenyl isobutylsulfonyl Dihydropyridazinone phenyltrifluoromethyl Dihydropyridazinone phenyl carboxamidobenzylDihydropyridazinone phenyl carboxamidobutyl-2-yl Dihydropyridazinonephenyl isobutyramido Dihydropyridazinone phenyl isobutoxyDihydropyridazinone phenyl carboethoxy Dihydropyridazinone phenylcarboxyl Dihydropyridazinone phenyl amino Dihydroisoxazinone phenylhydroxy Dihydroisoxazinone phenyl isobutylsulfonyl Dihydroisoxazinonephenyl trifluoromethyl Dihydroisoxazinone phenyl carboxamidobenzylDihydroisoxazinone phenyl carboxamidobutyl-2-yl Dihydroisoxazinonephenyl isobutyramido Dihydroisoxazinone phenyl isobutoxyDihydroisoxazinone phenyl carboethoxy Dihydroisoxazinone phenyl carboxylDihydroisoxazinone phenyl amino Tetrahydrotriazinedione phenyl hydroxyTetrahydrotriazinedione phenyl isobutylsulfonyl Tetrahydrotriazinedionephenyl trifluoromethyl Tetrahydrotriazinedione phenyl carboxamidobenzylTetrahydrotriazinedione phenyl carboxamidobutyl-2-ylTetrahydrotriazinedione phenyl isobutyramido Tetrahydrotriazinedionephenyl isobutoxy Tetrahydrotriazinedione phenyl carboethoxyTetrahydrotriazinedione phenyl carboxyl Tetrahydrotriazinedione phenylamino Tetrahydrotriazinone phenyl hydroxy Tetrahydrotriazinone phenylisobutylsulfonyl Tetrahydrotriazinone phenyl trifluoromethylTetrahydrotriazinone phenyl carboxamidobenzyl Tetrahydrotriazinonephenyl carboxamidobutyl-2-yl Tetrahydrotriazinone phenyl isobutyramidoTetrahydrotriazinone phenyl isobutoxy Tetrahydrotriazinone phenylcarboethoxy Tetrahydrotriazinone phenyl carboxyl Tetrahydrotriazinonephenyl amino Piperidine phenyl hydroxy Piperidine phenylisobutylsulfonyl Piperidine phenyl trifluoromethyl Piperidine phenylcarboxamidobenzyl Piperidine phenyl carboxamidobutyl-2-yl Piperidinephenyl isobutyramido Piperidine phenyl isobutoxy Piperidine phenylcarboethoxy Piperidine phenyl carboxyl Piperidine phenyl aminoPiperazine phenyl hydroxy Piperazine phenyl isobutylsulfonyl Piperazinephenyl trifluoromethyl Piperazine phenyl carboxamidobenzyl Piperazinephenyl carboxamidobutyl-2-yl Piperazine phenyl isobutyramido Piperazinephenyl isobutoxy Piperazine phenyl carboethoxy Piperazine phenylcarboxyl Piperazine phenyl amino Piperidinone cycloalkyl hydroxyPiperidinone cycloalkyl isobutylsulfonyl Piperidinone cycloalkyltrifluoromethyl Piperidinone cycloalkyl carboxamidobenzyl Piperidinonecycloalkyl carboxamidobutyl-2-yl Piperidinone cycloalkyl isobutyramidoPiperidinone cycloalkyl isobutoxy Piperidinone cycloalkyl carboethoxyPiperidinone cycloalkyl carboxyl Piperidinone cycloalkyl aminoDihydropyrimidinone cycloalkyl hydroxy Dihydropyrimidinone cycloalkylisobutylsulfonyl Dihydropyrimidinone cycloalkyl trifluoromethylDihydropyrimidinone cycloalkyl carboxamidobenzyl Dihydropyrimidinonecycloalkyl carboxamidobutyl-2-yl Dihydropyrimidinone cycloalkylisobutyramido Dihydropyrimidinone cycloalkyl isobutoxyDihydropyrimidinone cycloalkyl carboethoxy Dihydropyrimidinonecycloalkyl carboxyl Dihydropyrimidinone cycloalkyl aminoTetrahydropyrimidinone cycloalkyl hydroxy Tetrahydropyrimidinonecycloalkyl isobutylsulfonyl Tetrahydropyrimidinone cycloalkyltrifluoromethyl Tetrahydropyrimidinone cycloalkyl carboxamidobenzylTetrahydropyrimidinone cycloalkyl carboxamidobutyl-2-ylTetrahydropyrimidinone cycloalkyl isobutyramido Tetrahydropyrimidinonecycloalkyl isobutoxy Tetrahydropyrimidinone cycloalkyl carboethoxyTetrahydropyrimidinone cycloalkyl carboxyl Tetrahydropyrimidinonecycloalkyl amino Dehydropiperidinedione cycloalkyl hydroxyDehydropiperidinedione cycloalkyl isobutylsulfonylDehydropiperidinedione cycloalkyl trifluoromethyl Dehydropiperidinedionecycloalkyl carboxamidobenzyl Dehydropiperidinedione cycloalkylcarboxamidobutyl-2-yl Dehydropiperidinedione cycloalkyl isobutyramidoDehydropiperidinedione cycloalkyl isobutoxy Dehydropiperidinedionecycloalkyl carboethoxy Dehydropiperidinedione cycloalkyl carboxylDehydropiperidinedione cycloalkyl amino Dihydropyridazinone cycloalkylhydroxy Dihydropyridazinone cycloalkyl isobutylsulfonylDihydropyridazinone cycloalkyl trifluoromethyl Dihydropyridazinonecycloalkyl carboxamidobenzyl Dihydropyridazinone cycloalkylcarboxamidobutyl-2-yl Dihydropyridazinone cycloalkyl isobutyramidoDihydropyridazinone cycloalkyl isobutoxy Dihydropyridazinone cycloalkylcarboethoxy Dihydropyridazinone cycloalkyl carboxyl Dihydropyridazinonecycloalkyl amino Dihydroisoxazinone cycloalkyl hydroxyDihydroisoxazinone cycloalkyl isobutylsulfonyl Dihydroisoxazinonecycloalkyl trifluoromethyl Dihydroisoxazinone cycloalkylcarboxamidobenzyl Dihydroisoxazinone cycloalkyl carboxamidobutyl-2-ylDihydroisoxazinone cycloalkyl isobutyramido Dihydroisoxazinonecycloalkyl isobutoxy Dihydroisoxazinone cycloalkyl carboethoxyDihydroisoxazinone cycloalkyl carboxyl Dihydroisoxazinone cycloalkylamino Tetrahydrotriazinedione cycloalkyl hydroxy Tetrahydrotriazinedionecycloalkyl isobutylsulfonyl Tetrahydrotriazinedione cycloalkyltrifluoromethyl Tetrahydrotriazinedione cycloalkyl carboxamidobenzylTetrahydrotriazinedione cycloalkyl carboxamidobutyl-2-ylTetrahydrotriazinedione cycloalkyl isobutyramido Tetrahydrotriazinedionecycloalkyl isobutoxy Tetrahydrotriazinedione cycloalkyl carboethoxyTetrahydrotriazinedione cycloalkyl carboxyl Tetrahydrotriazinedionecycloalkyl amino Tetrahydrotriazinone cycloalkyl hydroxyTetrahydrotriazinone cycloalkyl isobutylsulfonyl Tetrahydrotriazinonecycloalkyl trifluoromethyl Tetrahydrotriazinone cycloalkylcarboxamidobenzyl Tetrahydrotriazinone cycloalkyl carboxamidobutyl-2-ylTetrahydrotriazinone cycloalkyl isobutyramido Tetrahydrotriazinonecycloalkyl isobutoxy Tetrahydrotriazinone cycloalkyl carboethoxyTetrahydrotriazinone cycloalkyl carboxyl Tetrahydrotriazinone cycloalkylamino Piperidine cycloalkyl hydroxy Piperidine cycloalkylisobutylsulfonyl Piperidine cycloalkyl trifluoromethyl Piperidinecycloalkyl carboxamidobenzyl Piperidine cycloalkyl carboxamidobutyl-2-ylPiperidine cycloalkyl isobutyramido Piperidine cycloalkyl isobutoxyPiperidine cycloalkyl carboethoxy Piperidine cycloalkyl carboxylPiperidine cycloalkyl amino Piperazine cycloalkyl hydroxy Piperazinecycloalkyl isobutylsulfonyl Piperazine cycloalkyl trifluoromethylPiperazine cycloalkyl carboxamidobenzyl Piperazine cycloalkylcarboxamidobutyl-2-yl Piperazine cycloalkyl isobutyramido Piperazinecycloalkyl isobutoxy Piperazine cycloalkyl carboethoxy Piperazinecycloalkyl carboxyl Piperazine cycloalkyl amino Piperidinone substitutedhydroxy cycloalkyl Piperidinone substituted isobutylsulfonyl cycloalkylPiperidinone substituted trifluoromethyl cycloalkyl Piperidinonesubstituted carboxamidobenzyl cycloalkyl Piperidinone substitutedcarboxamidobutyl-2-yl cycloalkyl Piperidinone substituted isobutyramidocycloalkyl Piperidinone substituted isobutoxy cycloalkyl Piperidinonesubstituted carboethoxy cycloalkyl Piperidinone substituted carboxylcycloalkyl Piperidinone substituted amino cycloalkyl Dihydropyrimidinonesubstituted hydroxy cycloalkyl Dihydropyrimidinone substitutedisobutylsulfonyl cycloalkyl Dihydropyrimidinone substitutedtrifluoromethyl cycloalkyl Dihydropyrimidinone substitutedcarboxamidobenzyl cycloalkyl Dihydropyrimidinone substitutedcarboxamidobutyl-2-yl cycloalkyl Dihydropyrimidinone substitutedisobutyramido cycloalkyl Dihydropyrimidinone substituted isobutoxycycloalkyl Dihydropyrimidinone substituted carboethoxy cycloalkylDihydropyrimidinone substituted carboxyl cycloalkyl Dihydropyrimidinonesubstituted amino cycloalkyl Tetrahydropyrimidinone substituted hydroxycycloalkyl Tetrahydropyrimidinone substituted isobutylsulfonylcycloalkyl Tetrahydropyrimidinone substituted trifluoromethyl cycloalkylTetrahydropyrimidinone substituted carboxamidobenzyl cycloalkylTetrahydropyrimidinone substituted carboxamidobutyl-2-yl cycloalkylTetrahydropyrimidinone substituted isobutyramido cycloalkylTetrahydropyrimidinone substituted isobutoxy cycloalkylTetrahydropyrimidinone substituted carboethoxy cycloalkylTetrahydropyrimidinone substituted carboxyl cycloalkylTetrahydropyrimidinone substituted amino cycloalkylDehydropiperidinedione substituted hydroxy cycloalkylDehydropiperidinedione substituted isobutylsulfonyl cycloalkylDehydropiperidinedione substituted trifluoromethyl cycloalkylDehydropiperidinedione substituted carboxamidobenzyl cycloalkylDehydropiperidinedione substituted carboxamidobutyl-2-yl cycloalkylDehydropiperidinedione substituted isobutyramido cycloalkylDehydropiperidinedione substituted isobutoxy cycloalkylDehydropiperidinedione substituted carboethoxy cycloalkylDehydropiperidinedione substituted carboxyl cycloalkylDehydropiperidinedione substituted amino cycloalkyl Dihydropyridazinonesubstituted hydroxy cycloalkyl Dihydropyridazinone substitutedisobutylsulfonyl cycloalkyl Dihydropyridazinone substitutedtrifluoromethyl cycloalkyl Dihydropyridazinone substitutedcarboxamidobenzyl cycloalkyl Dihydropyridazinone substitutedcarboxamidobutyl-2-yl cycloalkyl Dihydropyridazinone substitutedisobutyramido cycloalkyl Dihydropyridazinone substituted isobutoxycycloalkyl Dihydropyridazinone substituted carboethoxy cycloalkylDihydropyridazinone substituted carboxyl cycloalkyl Dihydropyridazinonesubstituted amino cycloalkyl Dihydroisoxazinone substituted hydroxycycloalkyl Dihydroisoxazinone substituted isobutylsulfonyl cycloalkylDihydroisoxazinone substituted trifluoromethyl cycloalkylDihydroisoxazinone substituted carboxamidobenzyl cycloalkylDihydroisoxazinone substituted carboxamidobutyl-2-yl cycloalkylDihydroisoxazinone substituted isobutyramido cycloalkylDihydroisoxazinone substituted isobutoxy cycloalkyl Dihydroisoxazinonesubstituted carboethoxy cycloalkyl Dihydroisoxazinone substitutedcarboxyl cycloalkyl Dihydroisoxazinone substituted amino cycloalkylTetrahydrotriazinedione substituted hydroxy cycloalkylTetrahydrotriazinedione substituted isobutylsulfonyl cycloalkylTetrahydrotriazinedione substituted trifluoromethyl cycloalkylTetrahydrotriazinedione substituted carboxamidobenzyl cycloalkylTetrahydrotriazinedione substituted carboxamidobutyl-2-yl cycloalkylTetrahydrotriazinedione substituted isobutyramido cycloalkylTetrahydrotriazinedione substituted isobutoxy cycloalkylTetrahydrotriazinedione substituted carboethoxy cycloalkylTetrahydrotriazinedione substituted carboxyl cycloalkylTetrahydrotriazinedione substituted amino cycloalkylTetrahydrotriazinone substituted hydroxy cycloalkyl Tetrahydrotriazinonesubstituted isobutylsulfonyl cycloalkyl Tetrahydrotriazinone substitutedtrifluoromethyl cycloalkyl Tetrahydrotriazinone substitutedcarboxamidobenzyl cycloalkyl Tetrahydrotriazinone substitutedcarboxamidobutyl-2-yl cycloalkyl Tetrahydrotriazinone substitutedisobutyramido cycloalkyl Tetrahydrotriazinone substituted isobutoxycycloalkyl Tetrahydrotriazinone substituted carboethoxy cycloalkylTetrahydrotriazinone substituted carboxyl cycloalkylTetrahydrotriazinone substituted amino cycloalkyl Piperidine substitutedhydroxy cycloalkyl Piperidine substituted isobutylsulfonyl cycloalkylPiperidine substituted trifluoromethyl cycloalkyl Piperidine substitutedcarboxamidebenzyl cycloalkyl Piperidine substitutedcarboxamidebutyl-2-yl cycloalkyl Piperidine substituted isobutyramidecycloalkyl Piperidine substituted isobutoxy cycloalkyl Piperidinesubstituted carboethoxy cycloalkyl Piperidine substituted carboxylcycloalkyl Piperidine substituted amino cycloalkyl Piperazinesubstituted hydroxy cycloalkyl Piperazine substituted isobutylsulfonylcycloalkyl Piperazine substituted trifluoromethyl cycloalkyl Piperazinesubstituted carboxamidobenzyl cycloalkyl Piperazine substitutedcarboxamidobutyl-2-yl cycloalkyl Piperazine substituted isobutyramidocycloalkyl Piperazine substituted isobutoxy cycloalkyl Piperazinesubstituted carboethoxy cycloalkyl Piperazine substituted carboxylcycloalkyl Piperazine substituted amino cycloalkyl

In a perfect embodiment, the compounds correspound to any of Formulae A,B, C, or D and the core, Z₁ and R₄₄ are as identified in Table 2.

TABLE 2 Core Z₁ R₄₄ Piperidinone methyl, ethyl, isopropyl, hydroxycyclopropyl, cyclobutyl, or phenyl Piperidinone methyl, ethyl,isopropyl, isobutylsulfonyl cyclopropyl, cyclobutyl, or phenylPiperidinone methyl, ethyl, isopropyl, trifluoromethyl cyclopropyl,cyclobutyl, or phenyl Piperidinone methyl, ethyl, isopropyl,carboxamidobenzyl cyclopropyl, cyclobutyl, or phenyl Piperidinonemethyl, ethyl, isopropyl, carboxamidobutyl-2-yl cyclopropyl, cyclobutyl,or phenyl Piperidinone methyl, ethyl, isopropyl, isobutyramidocyclopropyl, cyclobutyl, or phenyl Piperidinone methyl, ethyl,isopropyl, carboethoxy cyclopropyl, cyclobutyl, or phenyl Piperidinonemethyl, ethyl, isopropyl, carboxyl cyclopropyl, cyclobutyl, or phenylPiperidinone methyl, ethyl, isopropyl, amino cyclopropyl, cyclobutyl, orphenyl Dihydro- methyl, ethyl, isopropyl, hydroxy pyrimidinonecyclopropyl, cyclobutyl, or phenyl Dihydro- methyl, ethyl, isopropyl,isobutylsulfonyl pyrimidinone cyclopropyl, cyclobutyl, or phenylDihydro- methyl, ethyl, isopropyl, trifluoromethyl pyrimidinonecyclopropyl, cyclobutyl, or phenyl Dihydro- methyl, ethyl, isopropyl,carboxamidobenzyl pyrimidinone cyclopropyl, cyclobutyl, or phenylDihydro- methyl, ethyl, isopropyl, carboxamidobutyl-2-yl pyrimidinonecyclopropyl, cyclobutyl, or phenyl Dihydro- methyl, ethyl, isopropyl,isobutyramido pyrimidinone cyclopropyl, cyclobutyl, or phenyl Dihydro-methyl, ethyl, isopropyl, isobutoxy pyrimidinone cyclopropyl,cyclobutyl, or phenyl Dihydro- methyl, ethyl, isopropyl, carboethoxypyrimidinone cyclopropyl, cyclobutyl, or phenyl Dihydropyrimi- methyl,ethyl, isopropyl, carboxyl dinone cyclopropyl, cyclobutyl, or phenylDihydro- methyl, ethyl, isopropyl, amino pyrimidinone cyclopropyl,cyclobutyl, or phenyl Tetrahydro- methyl, ethyl, isopropyl, hydroxypyrimidinone cyclopropyl, cyclobutyl, or phenyl Tetrahydro- methyl,ethyl, isopropyl, isobutylsulfonyl pyrimidinone cyclopropyl, cyclobutyl,or phenyl Tetrahydro- methyl, ethyl, isopropyl, trifluoromethylpyrimidinone cyclopropyl, cyclobutyl, or phenyl Tetrahydro- methyl,ethyl, isopropyl, carboxamidobenzyl pyrimidinone cyclopropyl,cyclobutyl, or phenyl Tetrahydro- methyl, ethyl, isopropyl,carboxamidobutyl-2-yl pyrimidinone cyclopropyl, cyclobutyl, or phenylTetrahydro- methyl, ethyl, isopropyl, isobutyramido pyrimidinonecyclopropyl, cyclobutyl, or phenyl Tetrahydro- methyl, ethyl, isopropyl,isobutoxy pyrimidinone cyclopropyl, cyclobutyl, or phenyl Tetrahydro-methyl, ethyl, isopropyl, carboethoxy pyrimidinone cyclopropyl,cyclobutyl, or phenyl Tetrahydro- methyl, ethyl, isopropyl, carboxylpyrimidinone cyclopropyl, cyclobutyl, or phenyl Tetrahydro- methyl,ethyl, isopropyl, amino pyrimidinone cyclopropyl, cyclobutyl, or phenylDehydro- methyl, ethyl, isopropyl, hydroxy piperidine- cyclopropyl,cyclobutyl, dione or phenyl Dehydro- methyl, ethyl, isopropyl,isobutylsulfonyl piperidine- cyclopropyl, cyclobutyl, dione or phenylDehydro- methyl, ethyl, isopropyl, trifluoromethyl piperidine-cyclopropyl, cyclobutyl, dione or phenyl Dehydro- methyl, ethyl,isopropyl, carboxamidobenzyl piperidine- cyclopropyl, cyclobutyl, dioneor phenyl Dehydro- methyl, ethyl, isopropyl, carboxamidobutyl-2-ylpiperidine- cyclopropyl, cyclobutyl, dione or phenyl Dehydro- methyl,ethyl, isopropyl, isobutyramido piperidine- cyclopropyl, cyclobutyl,dione or phenyl Dehydro- methyl, ethyl, isopropyl, isobutoxy piperidine-cyclopropyl, cyclobutyl, dione or phenyl Dehydro- methyl, ethyl,isopropyl, carboethoxy piperidine- cyclopropyl, cyclobutyl, dione orphenyl Dehydro- methyl, ethyl, isopropyl, carboxyl piperidine-cyclopropyl, cyclobutyl, dione or phenyl Dehydro- methyl, ethyl,isopropyl, amino piperidine- cyclopropyl, cyclobutyl, dione or phenylDihydro- methyl, ethyl, isopropyl, hydroxy pyridazinone cyclopropyl,cyclobutyl, or phenyl Dihydro- methyl, ethyl, isopropyl,isobutylsulfonyl pyridazinone cyclopropyl, cyclobutyl, or phenylDihydro- methyl, ethyl, isopropyl, trifluoromethyl pyridazinonecyclopropyl, cyclobutyl, or phenyl Dihydro- methyl, ethyl, isopropyl,carboxamidobenzyl pyridazinone cyclopropyl, cyclobutyl, or phenylDihydro- methyl, ethyl, isopropyl, carboxamidobutyl-2-yl pyridazinonecyclopropyl, cyclobutyl, or phenyl Dihydro- methyl, ethyl, isopropyl,isobutyramido pyridazinone cyclopropyl, cyclobutyl, or phenyl Dihydro-methyl, ethyl, isopropyl, isobutoxy pyridazinone cyclopropyl,cyclobutyl, or phenyl Dihydro- methyl, ethyl, isopropyl, carboethoxypyridazinone cyclopropyl, cyclobutyl, or phenyl Dihydro- methyl, ethyl,isopropyl, carboxyl pyridazinone cyclopropyl, cyclobutyl, or phenylDihydro- methyl, ethyl, isopropyl, amino pyridazinone cyclopropyl,cyclobutyl, or phenyl Dihydro- methyl, ethyl, isopropyl, hydroxyisoxazinone cyclopropyl, cyclobutyl, or phenyl Dihydro- methyl, ethyl,isopropyl, isobutylsulfonyl isoxazinone cyclopropyl, cyclobutyl, orphenyl Dihydro- methyl, ethyl, isopropyl, trifluoromethyl isoxazinonecyclopropyl, cyclobutyl, or phenyl Dihydro- methyl, ethyl, isopropyl,carboxamidobenzyl isoxazinone cyclopropyl, cyclobutyl, or phenylDihydro- methyl, ethyl, isopropyl, carboxamidobutyl-2-yl isoxazinonecyclopropyl, cyclobutyl, or phenyl Dihydro- methyl, ethyl, isopropyl,isobutyramido isoxazinone cyclopropyl, cyclobutyl, or phenyl Dihydro-methyl, ethyl, isopropyl, isobutoxy isoxazinone cyclopropyl, cyclobutyl,or phenyl Dihydro- methyl, ethyl, isopropyl, carboethoxy isoxazinonecyclopropyl, cyclobutyl, or phenyl Dihydro- methyl, ethyl, isopropyl,carboxyl isoxazinone cyclopropyl, cyclobutyl, or phenyl Dihydro- methyl,ethyl, isopropyl, amino isoxazinone cyclopropyl, cyclobutyl, or phenylTetrahydro- methyl, ethyl, isopropyl, hydroxy triazinedione cyclopropyl,cyclobutyl, or phenyl Tetrahydro- methyl, ethyl, isopropyl,isobutylsulfonyl triazinedione cyclopropyl, cyclobutyl, or phenylTetrahydro- methyl, ethyl, isopropyl, trifluoromethyl triazinedionecyclopropyl, cyclobutyl, or phenyl Tetrahydro- methyl, ethyl, isopropyl,carboxamidobenzyl triazinedione cyclopropyl, cyclobutyl, or phenylTetrahydro- methyl, ethyl, isopropyl, carboxamidobutyl-2-yltriazinedione cyclopropyl, cyclobutyl, or phenyl Tetrahydro- methyl,ethyl, isopropyl, isobutyramido triazinedione cyclopropyl, cyclobutyl,or phenyl Tetrahydro- methyl, ethyl, isopropyl, isobutoxy triazinedionecyclopropyl, cyclobutyl, or phenyl Tetrahydro- methyl, ethyl, isopropyl,carboethoxy triazinedione cyclopropyl, cyclobutyl, or phenyl Tetrahydro-methyl, ethyl, isopropyl, carboxyl triazinedione cyclopropyl,cyclobutyl, or phenyl Tetrahydro- methyl, ethyl, isopropyl, aminotriazinedione cyclopropyl, cyclobutyl, or phenyl Tetrahydro- methyl,ethyl, isopropyl, hydroxy triazinone cyclopropyl, cyclobutyl, or phenylTetrahydro- methyl, ethyl, isopropyl, isobutylsulfonyl triazinonecyclopropyl, cyclobutyl, or phenyl Tetrahydro- methyl, ethyl, isopropyl,trifluoromethyl triazinone cyclopropyl, cyclobutyl, or phenylTetrahydro- methyl, ethyl, isopropyl, carboxamidobenzyl triazinonecyclopropyl, cyclobutyl, or phenyl Tetrahydro- methyl, ethyl, isopropyl,carboxamidobutyl-2-yl triazinone cyclopropyl, cyclobutyl, or phenylTetrahydro- methyl, ethyl, isopropyl, isobutyramido triazinonecyclopropyl, cyclobutyl, or phenyl Tetrahydro- methyl, ethyl, isopropyl,isobutoxy triazinone cyclopropyl, cyclobutyl, or phenyl Tetrahydro-methyl, ethyl, isopropyl, carboethoxy triazinone cyclopropyl,cyclobutyl, or phenyl Tetrahydro- methyl, ethyl, isopropyl, carboxyltriazinone cyclopropyl, cyclobutyl, or phenyl Tetrahydro- methyl, ethyl,isopropyl, amino triazinone cyclopropyl, cyclobutyl, or phenylPiperidine methyl, ethyl, isopropyl, hydroxy cyclopropyl, cyclobutyl, orphenyl Piperidine methyl, ethyl, isopropyl, isobutylsulfonylcyclopropyl, cyclobutyl, or phenyl Piperidine methyl, ethyl, isopropyl,trifluoromethyl cyclopropyl, cyclobutyl, or phenyl Piperidine methyl,ethyl, isopropyl, carboxamidobenzyl cyclopropyl, cyclobutyl, or phenylPiperidine methyl, ethyl, isopropyl, carboxamidobutyl-2-yl cyclopropyl,cyclobutyl, or phenyl Piperidine methyl, ethyl, isopropyl, isobutyramidocyclopropyl, cyclobutyl, or phenyl Piperidine methyl, ethyl, isopropyl,isobutoxy cyclopropyl, cyclobutyl, or phenyl Piperidine methyl, ethyl,isopropyl, carboethoxy cyclopropyl, cyclobutyl, or phenyl Piperidinemethyl, ethyl, isopropyl, carboxyl cyclopropyl, cyclobutyl, or phenylPiperidine methyl, ethyl, isopropyl, amino cyclopropyl, cyclobutyl, orphenyl Piperazine methyl, ethyl, isopropyl, hydroxy cyclopropyl,cyclobutyl, or phenyl Piperazine methyl, ethyl, isopropyl,isobutylsulfonyl cyclopropyl, cyclobutyl, or phenyl Piperazine methyl,ethyl, isopropyl, trifluoromethyl cyclopropyl, cyclobutyl, or phenylPiperazine methyl, ethyl, isopropyl, carboxamidobenzyl cyclopropyl,cyclobutyl, or phenyl Piperazine methyl, ethyl, isopropyl,carboxamidobutyl-2-yl cyclopropyl, cyclobutyl, or phenyl Piperazinemethyl, ethyl, isopropyl, isobutyramido cyclopropyl, cyclobutyl, orphenyl Piperazine methyl, ethyl, isopropyl, isobutoxy cyclopropyl,cyclobutyl, or phenyl Piperazine methyl, ethyl, isopropyl, carboethoxycyclopropyl, cyclobutyl, or phenyl Piperazine methyl, ethyl, isopropyl,carboxyl cyclopropyl, cyclobutyl, or phenyl Piperazine methyl, ethyl,isopropyl, amino cyclopropyl, cyclobutyl, or phenyl

For convenience, each of the core heterocyclic rings and R₄₄ moietiesidentified in Tables 1 and 2 are set forth below.

In another preferred embodiment, the compounds corresponding to eitherof formulas (1) and (2) are selected from the group of compoundsillustrated in Table 3 below wherein for any given compound, Z₁ isisopropyl, cyclopropyl, cyclobutyl, trifluoroethyl, or carboxymethyl.

TABLE 3 Compound No. Compound 1

2

3

4

5

6

7

8

9

10

Any prodrug compound of the present invention having one or more prodrugmoieties as part of the molecule, can be converted under physiologicalconditions to the biologically active drug by a number of chemical andbiological mechanisms. In general terms, as detailed above, theseprodrug conversion mechanisms are hydrolysis, reduction, oxidation, andelimination. For illustrative purposes, the following paragraphs detailprodrugs in which the prodrug moiety is covalently bonded to the amidinegroup on Z₃.

In one embodiment, conversion of the prodrug to the biologically activedrug can be accomplished by hydrolysis of the prodrug moiety providedthe prodrug moiety is chemically or enzymatically hydrolyzable withwater. The reaction with water typically results in removal of theprodrug moiety and liberation of the biologically active drug. By way ofexample, a hydrolyzable prodrug derivative at the amidine group may be acarbonyl derivative such as N-acyl. Hydrolysis results in freeing theamidine group of the drug by removal of the acyl as carbon acid. Othersuitable hydrolyzable prodrug derivatives include carbonyl,thiocarbonyl, imine, enamine, and oxygenated sulfur.

Yet another aspect of the invention provides conversion of the prodrugto the biologically active drug by reduction of the prodrug moiety.Typically in this embodiment, the prodrug moiety is reducible underphysiological conditions in the presence of a reducing enzymaticprocess. The reduction preferably results in removal of the prodrugmoiety and liberation of the biologically active drug. An example of areducible prodrug derivative at the amidine group is an oxygencontaining group in which an oxygen is directly attached to the amidine.Reduction results in freeing the amidine group of the drug by removal ofoxygen as water or an alcohol. Generally speaking, other suitablereducible prodrug derivatives include a nitrogen containing group, and asulfur containing group, provided both nitrogen and sulfur are eachpreferably in their most reduced state.

In another aspect of the invention, conversion of the prodrug to thebiologically active drug can also be accomplished by oxidation of theprodrug moiety. Typically in this embodiment, the prodrug moiety isoxidizable under physiological conditions in the presence of anoxidative enzymatic process. The oxidation preferably results in removalof the prodrug moiety and liberation of the biologically active drug. Anexample of an oxidizable prodrug derivative at the amidine group is ahydrocarbyl containing unsaturation in the carbon beta to the carbondirectly connected to the amidine group. Oxidation results in forming anoxygenated intermediate that breaks down, thereby freeing the amidinegroup of the drug with concurrent hydrolysis of the oxygenatedhydrocarbyl residue. Other suitable oxidizable prodrug derivatives ofthe amidine include saturated hydrocarbyl, unsaturated substitutedhydrocarbyl, aryl, and aralkyl.

A further aspect of the invention encompasses conversion of the prodrugto the biologically active drug by elimination of the prodrug moiety.Generally speaking, in this embodiment the prodrug moiety is removedunder physiological conditions with a chemical or biological reaction.The elimination results in removal of the prodrug moiety and liberationof the biologically active drug. By way of example, an eliminateableprodrug derivative at the amidine group is a hydrocarbyl containing anunsaturated electron withdrawing group bonded to the carbon beta to thecarbon directly connected to the amidine. More specifically, forillustration purposes and exemplification, the hydrocarbyl group couldhave a cyano group beta to the carbon directly bonded to the amidinogroup. Elimination results in the freeing of the amidine group of thedrug with concurrent removal of the unsaturated hydrocarbyl residuederived from the prodrug moiety. Other suitable eliminateable prodrugderivatives of the amidine include a hydrocarbyl substituted at the betacarbon with carbonyl, alkoxycarbonyl, amidocarbonyl, nitro, or sulfonylor an alkyl group substituted with oxygen, nitrogen or sulfur at thecarbon directly bonded to the amidine group.

Any prodrug compound of the present invention may undergo anycombination of the above detailed mechanisms to convert the prodrug tothe biologically active compound. For example, a particular compound mayundergo hydrolysis, oxidation, elimination, and reduction to convert theprodrug to the biologically active compound. Equally, a particularcompound may undergo only one of these mechanisms to convert the prodrugto the biologically active compound.

As a further embodiment, compounds of the present invention or apharmaceutically-acceptable salt thereof, comprise a treatment andprophylaxis for thrombotic events resulting from coronary arterydisease, cerebrovascular disease and other coagulation cascade relateddisorders in a subject, comprising administering to the subject havingsuch disorder a therapeutically-effective amount of compounds of thepresent invention or a pharmaceutically-acceptable salt thereof.

In another aspect of the invention, the compounds may also be usedwhenever inhibition of blood coagulation is required such as to preventcoagulation of stored whole blood and to prevent coagulation in otherbiological samples for testing or storage. Thus coagulation inhibitorsof the present inhibition can be added to or contacted with stored wholeblood and any medium containing or suspected of containing plasmacoagulation factors and in which it is desired that blood coagulation beinhibited, e.g. when contacting the mammal's blood with materialselected from the group consisting of vascular grafts, stents,orthopedic prothesis, cardiac prosthesis, and extracorporeal circulationsystems.

Compounds of the invention are capable of inhibiting activity of serineproteases related to the coagulation cascade, and thus could be used inthe manufacture of a medicament, a method for the prophylactic ortherapeutic treatment of diseases mediated by coagulation cascade serineproteases, such as inhibiting the formation of blood plateletaggregates, inhibiting the formation of fibrin, inhibiting thrombusformation, and inhibiting embolus formation in a mammal, in blood, inblood products, and in mammalian organs. The compounds also can be usedfor treating or preventing unstable angina, refractory angina,myocardial infarction, transient ischemic attacks, atrial fibrillation,thrombotic stroke, embolic stroke, deep vein thrombosis, disseminatedintravascular coagulation, ocular build up of fibrin, and reocclusion orrestenosis of recanalized vessels in a mammal. The compounds also can beused to study the mechanism of action of coagulation cascade serineproteases to enable the design of better inhibitors and development ofbetter assay methods. The compounds would be also useful in preventionof cerebral vascular accident (CVA) or stroke.

Also included in the family of compounds are thepharmaceutically-acceptable salts thereof. The term“pharmaceutically-acceptable salt” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of formulas (1), (2), or (3) may be preparedfrom an inorganic acid or from an organic acid. Examples of suchinorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric,carbonic, sulfuric and phosphoric acid. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which are formic, acetic, propionic, succinic, glycolic, gluconic,lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric,pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic,p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic,cyclohexylaminosulfonic, algenic, galacturonic acid. Suitablepharmaceutically-acceptable base addition salts of compounds of formulas(1), (2), or (3) include metallic salts made from aluminum, calcium,lithium, magnesium, potassium, sodium and zinc or organic salts madefrom N,N′-dibenzylethyleneldiamine, choline, chloroprocaine,diethanolamine, ethylenediamine, meglumine (N-methylglucamine) andprocain. All of these salts may be prepared by conventional means fromthe corresponding compound by reacting, for example, the appropriateacid or base with the compound of the present invention.

The present invention also comprises a pharmaceutical compositioncomprising a therapeutically-effective amount of the compound inassociation with at least one pharmaceutically-acceptable carrier,adjuvant or diluent. Pharmaceutical compositions of the presentinvention can comprise the active compounds in association with one ormore non-toxic, pharmaceutically-acceptable carriers and/or diluentsand/or adjuvants (collectively referred to herein as “carrier”materials) and, if desired, other active ingredients. The activecompounds of the present invention may be administered by any suitableroute, preferably in the form of a pharmaceutical composition adapted tosuch a route, and in a dose effective for the treatment intended.

The active compounds and composition may, for example, be administeredorally, intravascularly, intraperitoneally, subcutaneously,intramuscularly, oculary, or topically. For treating ocular build up offibrin, the compounds may be administered intraocularly or topically aswell as orally or parenterally.

The compounds can be administered in the form of a depot injection orimplant preparation which may be formulated in such a manner as topermit a sustained release of the active ingredient. The activeingredient can be compressed into pellets or small cylinders andimplanted subcutaneously or intramusculary as depot injections orimplants. Implants may employ inert materials such as biodegradablepolymers or synthetic silicones, for example, Silastic, silicone rubberor other silicon containing polymers.

The compounds can also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesiclesand multilamellar vesicles. Liposomes can be formed from a variety ofphospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds may also be delivered by the use of monoclonal antibodiesas individual carriers to which the compound molecules are coupled. Thecompounds may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or ployethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyglycolicacid, copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross linked or amphitpathicblock copolymers of hydrogels.

For oral administration, the pharmaceutical composition may be in theform of, for example, tablets, capsules (each of which includessustained release or timed release formulations), pills, powders,granules, elixers, tinctures, suspensions, liquids including syrups, andemulsions. The pharmaceutical composition is preferably made in the formof a dosage unit containing a particular amount of the activeingredient. Examples of such dosage units are tablets or capsules. Theactive ingredient may also be administered by injection as a compositionwherein, for example, saline, dextrose or water may be used as asuitable carrier.

The amount of therapeutically active compounds which are administeredand the dosage regimen for treating a disease condition with thecompounds and/or compositions of this invention depends on a variety offactors, including the age, weight, sex and medical condition of thesubject, the severity of the disease, the route and frequency ofadministration, and the particular compound employed, and thus may varywidely.

The pharmaceutical compositions may contain active ingredients in therange of about 0.1 to 2000 mg, and preferably in the range of about 0.5to 500 mg. A daily dose of about 0.01 to 100 mg/kg body weight, andpreferably between about 0.5 and about 20 mg/kg body weight, may beappropriate. The daily dose can be administered in one to four doses perday.

The compounds may be formulated in topical ointment or cream, or as asuppository, containing the active ingredients in a total amount of, forexample, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably0.4 to 15% w/w. When formulated in an ointment, the active ingredientsmay be employed with either paraffinic or a water-miscible ointmentbase.

Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example at least 30% w/w of a polyhydric alcoholsuch as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,polyethylene glycol and mixtures thereof. The topical formulation maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethylsulfoxide andrelated analogs. The compounds of this invention can also beadministered by a transdermal device. Preferably topical administrationwill be accomplished using a patch either of the reservoir and porousmembrane type or of a solid matrix variety. In either case, the activeagent is delivered continuously from the reservoir or microcapsulesthrough a membrane into the active agent permeable adhesive, which is incontact with the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as diisoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

For therapeutic purposes, the active compounds of the present inventionare ordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

In practicing the methods of the present invention for the treatment andprevention of a variety of thrombotic conditions resulting from coronaryartery and cerebrovascular disease, the compounds and pharmaceuticalcompositions of the present invention are administered alone or incombination with one another, or in combination with other therapeuticsor in vivo diagnostic agents. The coagulation cascade inhibitors of thepresent invention can also be co-administered with suitableanti-platelet aggregation agents, including, but not limited toticlopidine, clopidrogel, or aspirin, fibrinogen receptor antagonists(e.g., to treat or prevent unstable angina or to prevent reocculsionafter angioplasty and restenosis), anti-coagulants such as warfarin orheparins, thrombolytic agents such as plasminogen activators orstreptokinase to achieve synergistic effects in the treatment of variouspathologies, lipid lowering agents including antihypercholesterolemics(e.g., HMG CoA reductase inhibitors such as mevastatin, lovastatin,simvastatin, pravastatin, and fluvastatin, HMG CoA synthataseinhibitors, etc.), anti-diabetic drugs, or other cardiovascular agents(loop diuretics, thiazide type diuretics, nitrates, aldosteroneantagonistics (i.e., spironolactone and eplerenone), angiotensinconverting enzyme (ACE) inhibitors, angiotensin II receptor antagonists,beta-blockers, antiarrythmics, anti-hypertension agents, and calciumchannel blockers) to treat or prevent atheriosclerosis. For example,patients suffering from coronary artery disease, and patients subjectedto angioplasty procedures, would benefit from coadministration offibrinogen receptor antagonists and coagulation cascade inhibitors ofthe present invention. Also, coagulation cascade inhibitors couldenhance the efficiency of tissue plasminogen activator-mediatedthrombolytic reperfusion.

Typical doses of coagulation cascade inhibitors of the present inventionwith other suitable anti-platelet agents, anticoagulation agents,cardiovascular therapeutic agents, or thrombolytic agents may be thesame as those doses of coagulation cascade inhibitors administeredwithout coadministration of additional anti-platelet agents,anticoagulation agents, cardiovascular therapeutic agents, orthrombolytic agents, or may be substantially less than those doses ofcoagulation cascade inhibitors administered without coadministration ofadditional anti-platelet agents, anticoagulation agents, cardiovasculartherapeutic agents, or thrombolytic agents, depending on a patient'stherapeutic needs.

Compounds of the present invention can exist in tautomeric, geometric orstereoisomeric forms. The present invention contemplates all suchcompounds, including cis- and trans-geometric isomers, E- andZ-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers,1-isomers, the racemic mixtures thereof and other mixtures thereof, asfalling within the scope of the invention. Pharmaceutically acceptablesalts of such tautomeric, geometric or stereoisomeric forms are alsoincluded within the invention.

The terms “cis” and “trans”, as used herein, denote a form of geometricisomerism in which two carbon atoms connected by a double bond will eachhave a hydrogen atom on the same side of the double bond (“sis”) or onopposite sides of the double bond (“trans”).

Some of the compounds described contain alkenyl groups, and are meant toinclude both cis and trans or “E” and “Z” geometric forms.

Some of the compounds described contain one or more stereocenters andare meant to include R, S, and mixtures of R and S forms for eachstereocenter present.

The present novel methods preferably employ compounds which selectivelyinhibit human TF-VIIa over the inhibition of both human Thrombin II andhuman factor Xa. Preferably, the compounds have a human TF-VIIa IC₅₀ ofless than 0.5 uM and also have a selectivity ratio of TF-VIIa inhibitionover both human Thrombin II and human factor Xa inhibition of at least10, and more preferably at least 100. Even more preferably, thecompounds have a human TF-VIIa IC₅₀ of less than 0.1 uM and also have aselectivity ratio of TF-VIIa inhibition over both human Thrombin II andhuman factor Xa inhibition of at least 300, more preferably at least1000, and most preferably at least 10,000.

All mentioned references are incorporated by reference as if herewritten.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations. Without further elaboration, it is believed that oneskilled in the art can, using the preceding descriptions, utilize thepresent invention to its fullest extent. Compounds containing multiplevariations of the structural modifications illustrated in the Schemesare also contemplated. Those skilled in the art will readily understandthat known variations of the conditions and processes of the followingpreparative procedures can be used to prepare these compounds.

GENERAL SYNTHETIC PROCEDURES AND SPECIFIC EXAMPLES

The compounds of the present invention can be synthesized, for example,according to the following procedures and Schemes given below.

Abbreviations used in the schemes and tables include: “AA” representsamino acids, “AcCN” represents acetonitrile, “AcOH” represents aceticacid, “BINAP” represents 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,“BnOH” represents benzyl alcohol, “BnCHO” represents 2-phenylethanal,“BnSO₂Cl” represents benzylsulfonyl chloride, “Boc” representstert-butyloxycarbonyl, “BOP” representsbenzotriazol-1-yl-oxy-tris-(dimethylamino), “bu” represents butyl, “dba”represents dibenzylidene-acetone, “DCC” represents1,3-dicyclohexylcarbodiimide, “DCM” represents dichloromethane ormethylene chloride, “DIBAH” or “DIBAL” represents diisobutylaluminumhydride, “DMF” represents dimethylformamide, “DMSO” representsdimethylsulfoxide, “DPPA” represents diphenylphosphoryl azide”, “EDC”represents 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride, “Ex. No.” represents Example Number, “Fmoc” represents9-fluorenylmethoxycarbonyl, “HOBt” represents hydroxybenzoltriazole”,“LDA” represents lithium diisopropylamide, “MW” represents molecularweight, “NMM” represents N-methylmorpholine, “Ph” represents phenyl oraryl, “PHTH” represents a phthaloyl group, “pnZ” represents4-nitrobenzyloxy-carbonyl, “PTC” represents a phase transfer catalyst,“py” represents pyridine, “RNH₂” represents a primary organic amine,“SEM” represents 2-(trimethylsilyl)ethoxy-methyl chloride, “p-TsOH”represents paratoluenesulfonic acid, “TBAF” representstetrabutylammonium fluoride, “TBTU” represents2-(1H-benzotriozole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate,“TEA” represents triethylamine, “TFA” represents trifluoroacetic acid,“THF” represents tetrahydrofuran, “TMS” represents trimethylsilyl,“TMSCN” represents trimethylsilyl cyanide, and “Cbz” or “Z” representsbenzyloxycarbonyl.

A specific synthetic process, useful in the preparation of many of theheterocyclic compounds of the present invention, is the arylation orheteroarylation of an intermediate compound characterized by having asuitable leaving group on a sp² hybridized carbon of a heterocyclic ringor a cycloalkenyl ring. In the product of the reaction, the leavinggroup is replaced by an aryl group or a heteroaryl group. Suitableleaving groups for the reaction include chloro, bromo, iodo, methylthio,and triflates. The heterocyclic ring or the cycloalkenyl ring with theleaving group will preferably have an acetic acid group or a derivativethereof bonded to a ring atom alpha to the bromo and a substituted orunsubstituted amino group bonded to a ring atom that is both beta to thecarbon having the acetic acid group and gamma to the bromo substitutedring carbon. The aryl group that is reacted at the sp² hybridized carbonis generally an aryl boronic acid or an ester of the aryl boronic acid;similarly, heteroaryl boronic acids or esters of these boronic acids canbe used in the same manner as aryl boronates. The aryl and heteroarylboronates may be substituted or unsubstituted. The aryl or heteroarylbecomes bonded to the sp² hybridized carbon at the point at which theboron was attached to the aryl or heteroaryl ring. Aryl and heteroarylorganoSn compounds can also be used instead of the correspondingboronates.

Suitable reaction conditions for carrying out this transformationinclude:

-   -   1. Pd[P(phenyl)₃]₄, 2M Na₂CO₃, 60-75° C., dimethoxyethane (DME),        H₂O, N₂;    -   2. Pd[P(phenyl)₃]₄, Cs₂CO₃, dioxane, 100° C.;    -   3. Pd[P(phenyl)₃]₄ Cu(I)-2-thiophenecarboxylate, 70-75° C.,        anhydrous THF, argon;    -   4. Z4-Sn(n-butyl)₃], Pd[P(phenyl)₃]₄, LiCl, anhydrous dioxane,        85° C., argon or N₂.        The organo palladium (Pd[P(phenyl)3]4) compound is used        catalytically in a ratio of 1 to 40 mole %. The carbonate base        is normally used in an excess of 1.2 to 2 molar equivalents.        Suitable solvents include dimethoxyethane (DME), dioxane,        1-propanol, and tetrahydrofuran. The temperature of the reaction        is normally in the range of from about 50 to 100° C.        Cu(I)-2-thiophenecarboxylate (Cu(I)-TC) is normally used in a        mole % of 110-150.

Schemes 2, 4, 5 and 6 show specific applications of this specificsynthetic process. Procedures for preparing the intermediateheterocyclic or cycloalkenyl ring compounds having a suitable leavinggroup on sp² hybridized carbon and useful as suitable intermediates inthis specific synthetic process are given in the schemes and exampleslisted above.

As used in the schemes and examples, L₃, Z₁, Z₃, Z₄, and R₄₄, along withany other variable depicted, encompass each group described for eachparticular variable for each embodiment of compounds having any of theformulas detailed herein. Further, Z₅ and Z₆ are independently hydrogenor halogen, R_(4a) and R_(4b) are hydrogen, and L₆ is a bond.

1. A compound having the structure:

wherein Z₁ is selected from the group consisting of an optionallysubstituted C₂ to C₈ alkyl, optionally substituted C₃ to C₆ cycloalkyland optionally substituted phenyl; Z₃ comprises a 5- or 6-memberedheterocyclic or aromatic ring substituted with an amidine or aderivatized amidine group which, upon hydrolysis, oxidation, reductionor elimination yields an amidine group, the ring atoms of the 5- or6-membered heterocyclic or aromatic ring of Z₃ being carbon, sulfur,nitrogen, or oxygen; Z₄ comprises a 5- or 6-membered heterocyclic orcarbocyclic ring, the ring atoms of Z₄ being Z₄₀, Z₄₁, Z₄₂, Z₄₄ and Z₄₅,when Z₄ is a 5-membered ring and Z₄₀, Z₄₁, Z₄₂, Z₄₃, Z₄₄ and Z₄₅ when Z₄is a 6-membered ring, Z₄₀, Z₄₁, Z₄₂, Z₄₃, Z₄₄ and Z₄₅, being carbon,nitrogen, oxygen or sulfur, Z₄₀ being the ring atom through which Z₄ isattached to the heterocyclic core ring, Z₄₁ and Z₄₅ each being in analpha position relative to Z₄₀, Z₄₂ and Z₄₄ each being in a betaposition relative to Z₄₀, Z₄₃ being in the gamma position relative toZ₄₀ when Z₄ is a 6-membered ring, Z₄ having a substituent R₄₂ covalentlyattached to Z₄₂, and a second substituent bonded to one of Z₄₁, Z₄₃,Z₄₄, or Z₄₅, the substituent being R₄₁ when bonded to Z₄₁, thesubstituent being R₄₃ when bonded to Z₄₃, the substituent being R₄₄ whenbonded to Z₄₄, and the substituent being R₄₅ when bonded to Z₄₅; R₄₂ isamino; and R₄₁, R₄₃, R₄₄ and R₄₅ are independently hydrogen,hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, or asubstituted or unsubstituted heteroatom selected from nitrogen, oxygen,sulfur and phosphorus, provided at least one of R₄₁, R₄₃, R₄₄ or R₄₅ isother than hydrogen.
 2. The compound of claim 1 wherein Z₁ is selectedfrom the group consisting of cyclopropyl, isopropyl, methyl, ethyl,cyclobutyl, isobutyl, tert-butyl, sec-butyl, and phenyl optionallysubstituted at any substitutable position with fluorine, hydroxy,carboxy or alkoxycarbonyl.
 3. The compound of claim 2 wherein Z₁ iscyclopropyl or isopropyl optionally substituted at any substitutableposition with fluorine, hydroxy, carboxy or alkoxycarbonyl.
 4. Thecompound of claim 1 wherein Z₃ comprises a substituted phenyl, thienyl,or furanyl ring, the phenyl, thienyl or furanyl ring being substitutedwith an amidine or a derivatized amidine group, and optionally furthersubstituted at any substitutable position with fluorine, hydroxy,carboxy, alkoxycarbonyl, or hydrocarbyloxy.
 5. The compound of claim 4wherein Z₃ is

wherein R₃₀₄ and R₃₀₆ are independently selected from the groupconsisting of hydrogen, fluorine, hydroxy, carboxy, hydrocarbyloxy andalkoxycarbonyl; and R₃₀₅ and R₃₀₇ are independently selected from thegroup consisting of hydrogen, fluorine, methoxy, hydroxy and carboxy. 6.The compound of claim 4 wherein the 5- or 6-membered heterocyclic oraromatic ring comprising Z₃ is substituted with a derivatized amidinewhich, upon hydrolysis, oxidation, reduction or elimination, or anycombination thereof, yields an amidine group.
 7. The compound of claim 1wherein Z₄ has the following structure:

wherein R₄₂ is amino; R₄₄ is hydrocarbyl, substituted hydrocarbyl,halogen or an optionally substituted heteroatom selected from the groupconsisting of oxygen, nitrogen, and sulfur; and R₄₁, R₄₃ and R₄₅ areindependently hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen oran optionally substituted heteroatom selected from the group consistingof oxygen, nitrogen, and sulfur.
 8. The compound of claim 7 wherein R₄₁,R₄₃ and R₄₅ are independently hydrogen, halogen, alkoxy, or alkyl,optionally substituted with halogen or alkoxy and R₄₂ and R₄₄ are asdefined in claim
 7. 9. The compound of claim 7 wherein R₄₄ is selectedfrom the group consisting of hydroxy, carboxy, carboxamido, alkoxy,alkylsulfonyl, sulfonamido, or alkoxycarbonyl.
 10. The compound of claim9 wherein R₄₄ is sec-butylamide, carboxy, ethoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isopropylamide or hydroxy.
 11. Thecompound of claim 1 wherein Z₄ has the following structure: wherein Z₄₀,Z₄₁, Z₄₂, Z₄₄, and Z₄₅ are independently selected from the groupconsisting of carbon, nitrogen, oxygen and sulfur; R₄₂ is amino; R₄₄ ishydrocarbyl, substituted hydrocarbyl, halogen or an optionallysubstituted heteroatom selected from the group consisting of oxygen,nitrogen, and sulfur; and R₄₁ and R₄₅ are independently hydrogen,hydrocarbyl, substituted hydrocarbyl, halogen or an optionallysubstituted heteroatom selected from the group consisting of oxygen,nitrogen, and sulfur.
 12. The compound of claim 11 wherein R₄₁ and R₄₅are independently hydrogen, halogen, alkoxy, or alkyl, optionallysubstituted with halogen or alkoxy and R₄₂ and R₄₄ are as defined inclaim
 11. 13. The compound of claim 11 wherein R₄₄ is selected from thegroup consisting of hydroxy, carboxy, carboxamido, alkoxy,alkylsulfonyl, sulfonamido, or alkoxycarbonyl.
 14. The compound of claim13 wherein R₄₄ is sec-butylamide, carboxy, ethoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isopropylamide or hydroxy.